Rituximab treatment in pediatric-onset multiple sclerosis.

BACKGROUND AND PURPOSE: Rituximab (RTX) is frequently used off-label in multiple sclerosis. However, studies on the risk-benefit profile of RTX in pediatric-onset multiple sclerosis are scarce. METHODS: In this multicenter retrospective cohort study, patients with pediatric-onset multiple sclerosis from Sweden, Austria and Germany, who received RTX treatment were identified by chart review. Annualized relapse rates, Expanded Disability Status Scale scores and magnetic resonance imaging parameters (new T2 lesions and contrast-enhancing lesions) were assessed before and during RTX treatment. The proportion of patients who remained free from clinical and disease activity (NEDA-3) during RTX treatment was calculated. Side effects such as infusion-related reactions, infections and laboratory abnormalities were assessed. RESULTS: Sixty-one patients received RTX during a median (interquartile range) follow-up period of 20.9 (35.6) months. The annualized relapse rate decreased from 0.6 (95% confidence interval [CI] 0.38-0.92) to 0.03 (95% CI 0.02-0.14). The annual rate of new T2 lesions decreased from 1.25 (95% CI 0.70-2.48) to 0.08 (95% CI 0.03-0.25) and annual rates of new contrast-enhancing lesions decreased from 0.86 (95% CI 0.30-3.96) to 0. Overall, 70% of patients displayed no evidence of disease activity (NEDA-3). Adverse events were observed in 67% of patients. Six patients discontinued treatment due to ongoing disease activity or adverse events. CONCLUSION: Our study provides class IV evidence that RTX reduces clinical and radiological activity in pediatric-onset multiple sclerosis.

Development and preliminary validation of the Sleep Screening for Children and Adolescents with Complex Chronic Conditions (SCAC).

Children and adolescents with complex chronic conditions, including those with life-threatening or life-limiting conditions, are a heterogeneous population. Many individuals exhibit sleep abnormalities that are measurable by proxy questionnaires. No suitable instrument to assess the wide range of different complex chronic conditions is currently available. The aim of the present study was to develop a screening tool-the Sleep Screening for Children and Adolescents with Complex Chronic Conditions-to effectively obtain sleep behaviour information in this population. Following a mixed-method design, potential items for the Sleep Screening for Children and Adolescents with Complex Chronic Conditions questionnaire were defined through literature research and expert meetings. In a pre-test with N = 60 family and professional caregivers, the items' relevance and comprehensibility as well as the instrument's overall design were assessed. For the main test, N = 315 participants were recruited in three tertiary paediatric hospitals. A principal components analysis detected the questionnaire's scales. Item analysis focused on mean values, range, difficulty and discriminatory power. Convergent validation of the Sleep Screening for Children and Adolescents with Complex Chronic Conditions was assessed via correlations between scale items. Most patients had neurological or neuromuscular diseases. Four scales ("Falling and staying asleep", "Sleep-associated respiration and arousal", "Daytime sleepiness" and "Sleep-associated movements") emerged. The item analysis showed satisfactory discriminative power. In the preliminary validation, all scales correlated positively with a child's care level and with various sleep circumstances items. Three scales additionally correlated with the number of complex chronic condition diagnoses. This newly developed questionnaire can provide clinicians with first indications of possible sleep problems in a growing paediatric population.

Serum neurofilament light-chain levels in children with monophasic myelin oligodendrocyte glycoprotein-associated disease, multiple sclerosis, and other acquired demyelinating syndrome.

OBJECTIVE: To assess the diagnostic and prognostic potential of serum neurofilament light chain (sNfL) in children with first acquired demyelinating syndrome (ADS). METHODS: We selected 129 children with first ADS including 19 children with myelin oligodendrocyte glycoprotein (MOG)-antibody associated disease (MOGAD), 36 MOG/AQP4-seronegative ADS, and 74 with multiple sclerosis (MS) from the BIOMARKER study cohort. All children had a complete set of clinical, radiological, laboratory data and serum for NfL measurement using a highly sensitive digital ELISA (SIMOA). A control group of 35 children with non-inflammatory neurological diseases was included. sNfL levels were compared across patient groups according to clinical, laboratory, neuroradiological features and outcome after 2 years. RESULTS: sNfL levels were significantly increased in MOGAD, seronegative ADS and MS compared to controls (p-value < 0.001), in particular in children with an acute disseminated encephalomyelitis (ADEM)-like magnetic resonance imaging (MRI) pattern (p < 0.001) or longitudinally extensive myelitis (p < 0.01). In pediatric MS, elevated sNfL levels were significantly associated with higher numbers of cerebral (p < 0.001) and presence of spinal (p < 0.05) MRI lesions at baseline and predicted a higher number of relapses (p < 0.05). CONCLUSION: sNfL levels are significantly elevated in all three studied pediatric ADS subtypes indicating neuroaxonal injury. In pediatric MS high levels of sNfL are associated with risk factors for disease progression.

[Practice-relevant autoimmune diseases of the central nervous system in pediatrics: early diagnosis and adequate initiation of treatment]. / Praxisrelevante autoimmune Erkrankungen des zentralen Nervensystems in der Pädiatrie: frühe Diagnose und adäquater Therapiebeginn.

BACKGROUND: Pediatric autoimmune diseases affecting the central nervous system have recently come into the the focus of attention. Important advances have been made in the field of children with multiple sclerosis (MS), which led to a better understanding of the clinical characteristics and treatment options. Furthermore, new autoantibodies against target antigens of neurons, peripheral nerves and the myelin sheath have been detected. OBJECTIVE: This article summarizes new advances in children with MS and addresses the differences to their adult counterparts. In addition, the most important forms of autoimmune encephalitis, such as N­methyl D­aspartate receptor (NMDA-R) or myelin oligodendrocyte glycoprotein (MOG) encephalitis in children are described together with the diagnostic algorithm and therapeutic approach in the event of a suspected autoimmune encephalitis. Lastly, the clinical spectrum of MOG antibody-associated diseases (MOGAD) is detailed.

Impaired Brain Growth in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Acute Disseminated Encephalomyelitis.

BACKGROUND AND OBJECTIVES: Acute disseminated encephalomyelitis (ADEM) is the most common phenotype in pediatric myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease. A previous study demonstrated impaired brain growth in ADEM. However, the effect of MOG antibodies on brain growth remains unknown. Here, we performed brain volume analyses in MOG-positive and MOG-negative ADEM at onset and over time. METHODS: In this observational cohort study, we included a total of 62 MRI scans from 24 patients with ADEM (54.2% female; median age 5 years), of which 16 (66.7%) were MOG positive. Patients were compared with healthy controls from the NIH pediatric MRI data repository and a matched local cohort. Mixed-effect models were applied to assess group differences and other relevant factors, including relapses. RESULTS: At baseline and before any steroid treatment, patients with ADEM, irrespective of MOG antibody status, showed reduced brain volume compared with matched controls (median [interquartile range] 1,741.9 cm3 [1,645.1-1,805.2] vs 1,810.4 cm3 [1,786.5-1,836.2]). Longitudinal analysis revealed reduced brain growth for both MOG-positive and MOG-negative patients with ADEM. However, MOG-negative patients showed a stronger reduction (-138.3 cm3 [95% CI -193.6 to -82.9]) than MOG-positive patients (-50.0 cm3 [-126.5 to -5.2]), independent of age, sex, and treatment. Relapsing patients (all MOG positive) showed additional brain volume loss (-15.8 cm3 [-68.9 to 37.3]). DISCUSSION: Patients with ADEM exhibit brain volume loss and failure of age-expected brain growth. Importantly, MOG-negative status was associated with a more pronounced brain volume loss compared with MOG-positive patients.

Retrospective Pediatric Cohort Study Validates NEOS Score and Demonstrates Applicability in Children With Anti-NMDAR Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is the most common form of autoimmune encephalitis in children and adults. Although our understanding of the disease mechanisms has progressed, little is known about estimating patient outcomes. Therefore, the NEOS (anti-NMDAR Encephalitis One-Year Functional Status) score was introduced as a tool to predict disease progression in NMDARE. Developed in a mixed-age cohort, it currently remains unclear whether NEOS can be optimized for pediatric NMDARE. METHODS: This retrospective observational study aimed to validate NEOS in a large pediatric-only cohort of 59 patients (median age of 8 years). We reconstructed the original score, adapted it, evaluated additional variables, and assessed its predictive power (median follow-up of 20 months). Generalized linear regression models were used to examine predictability of binary outcomes based on the modified Rankin Scale (mRS). In addition, neuropsychological test results were investigated as alternative cognitive outcome. RESULTS: The NEOS score reliably predicted poor clinical outcome (mRS ≥3) in children in the first year after diagnosis (p = 0.0014) and beyond (p = 0.036, 16 months after diagnosis). A score adapted to the pediatric cohort by adjusting the cutoffs of the 5 NEOS components did not improve predictive power. In addition to these 5 variables, further patient characteristics such as the "Herpes simplex virus encephalitis (HSE) status" and "age at disease onset" influenced predictability and could potentially be useful to define risk groups. NEOS also predicted cognitive outcome with higher scores associated with deficits of executive function (p = 0.048) and memory (p = 0.043). DISCUSSION: Our data support the applicability of the NEOS score in children with NMDARE. Although not yet validated in prospective studies, NEOS also predicted cognitive impairment in our cohort. Consequently, the score could help identify patients at risk of poor overall clinical outcome and poor cognitive outcome and thus aid in selecting not only optimized initial therapies for these patients but also cognitive rehabilitation to improve long-term outcomes.

MR imaging in children with transverse myelitis and acquired demyelinating syndromes.

BACKGROUND: Transverse myelitis (TM) occurs isolated or within other acquired demyelinating syndromes (ADS) such as neuromyelitis optica spectrum disorders (NMOSD), multiple sclerosis (MS) or myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD). OBJECTIVE: To describe and compare clinical and MRI features of children with ADS presenting with TM grouped according to antibody status and diagnosis of MS and NMOSD. PATIENTS AND METHODS: Children with TM, radiological involvement of the myelon, MOG and aquaporin-4 antibody status were elegible. RESULTS: 100 children were identified and divided into MOGAD (n=33), NMOSD (n=7), double seronegative TM (n=34), and MS (n=26). MOGAD children had mainly acute disseminated encephalomyelitis + TM/ longitudinally extensive TM (LETM) (42%) or isolated LETM (30%). In MOGAD, LETM was present in more than half of all children (55%) with predominant involvement of only the grey matter (73%). Leptomeningeal enhancement was highly predictive of MOGAD (16/30; p=0.003). In MS patients spinal MRI showed single (50%) or multiple short lesions (46%) with involvement of grey and white matter (68%). Double seronegative children presented with LETM (74%) and brain lesions were less frequent compared to the other groups (30%). CONCLUSION: Children with ADS presenting with TM reveal important radiological differences such as LETM with predominant involvement of spinal grey matter and leptomeningeal enhancement in MOGAD.

Mitochondrial diseases mimicking autoimmune diseases of the CNS and good response to steroids initially.

INTRODUCTION: Neuroimmunological diseases such as autoimmune encephalitis (AE) or acquired demyelinating syndromes (ADS), can present with neurological symptoms and imaging features that are indistinguishable from mitochondrial diseases (MD) in particular at initial presentation. METHODS: Retrospective analysis of the clinical, laboratory and neuroimaging features of five patients who presented with signs of a neuroimmunological disease but all had pathological pathogenic variants in genes related to mitochondrial energy metabolism. RESULTS: Four patients presented with an acute neurological episode reminiscent of a possible AE and one patient with a suspected ADS at initial presentation. MRI findings were compatible with neuroimmunological diseases in all patients. In two children cerebrospinal fluid (CSF) studies revealed a mildly elevated cell count, two had elevated CSF lactate, none had oligoclonal bands (OCBs). All patients improved rapidly with intravenous steroids or immunoglobulins. Four patients had one or more relapses. Three patients showed worsening of their neurological symptoms with subsequent episodes and one patient died. Relapses in conjunction with new and progressive neurological symptoms, led to additional work-up which finally resulted in different genetic diagnosis of MD in all patients (MT-TL1, MT-ND5, APOA1-BP, HPDL, POLG). DISCUSSION: We would like to draw attention to a subset of patients with MD initially presenting with signs and symptoms mimicking neuroimmunological. Absence of CSF pleocytosis, elevated CSF lactate and progressive, relapsing course should trigger further (genetic) investigations in search of a MD even in patients with good response initially to immunomodulating therapies.

Temporal Dynamics of MOG Antibodies in Children With Acquired Demyelinating Syndrome.

BACKGROUND AND OBJECTIVE: The spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (MOGAD) comprises monophasic diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and transverse myelitis and relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a first MOGAD are still lacking. The objective of the study is to assess the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG-IgG titers in children with MOGAD in correlation with clinical presentation and disease course. METHODS: In this prospective multicenter hospital-based study, children with a first demyelinating attack and complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data were included. Serum samples were analyzed by live cell-based assay, and a titer level of ≥1:160 was classified as MOG-IgG-positive. RESULTS: One hundred sixteen children (f:m = 57:59) with MOGAD were included and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), neuromyelitis optica spectrum disorder (n = 8) or encephalitis (n = 6). The median follow-up time was 3 years in monophasic and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Seroconversion to MOG-IgG-negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. Forty-two/one hundred sixteen patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the first and second years, often with seroconversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of ≥3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. In our cohort, no patient experienced a relapse after seroconversion to MOG-IgG-negative. DISCUSSION: In this study, patients with declining MOG-IgG titers, particularly those with seroconversion to MOG-IgG-negative, are shown to have a significantly reduced relapse risk.

Clinical and imaging features of children with autoimmune encephalitis and MOG antibodies.

OBJECTIVE: To describe the presentations, radiologic features, and outcomes of children with autoimmune encephalitis associated with myelin oligodendrocyte glycoprotein antibodies (MOG abs). METHODS: Identification of children fulfilling the diagnostic criteria for possible autoimmune encephalitis (AE) and testing positive for serum MOG abs. Chart review and comprehensive analysis of serum MOG abs using live cell assays and rat brain immunohistochemistry. RESULTS: Ten children (4 girls, 6 boys) with AE and serum MOG abs were identified. The median age at onset was 8.0 years (range: 4-16 years). Children presented with a combination of encephalopathy (10/10), headache (7/10), focal neurologic signs (7/10), or seizures (6/10). CSF pleocytosis was common (9/10, median 80 white cell count/µL, range: 21-256). Imaging showed cortical and deep gray matter involvement in all in addition to juxtacortical signal alterations in 6/10 children. No involvement of other white matter structures or contrast enhancement was noted. MOG abs were detected in all children (median titer 1:640; range: 1:320-1:10,540). Nine children had a favorable outcome at discharge (modified Rankin scale of < 2). Five of 10 children had up to 3 additional demyelinating relapses associated with persisting MOG abs. One child had NMDA receptor (NMDAR) abs at initial presentation. A second child had a third demyelinating episode with MOG abs with overlapping NMDAR encephalitis. DISCUSSION: AE associated with serum MOG abs represents a distinct form of autoantibody-mediated encephalitis in children. We therefore recommend including MOG abs testing in the workup of children with suspected AE.