Early predictors of epilepsy and subsequent relapse in children with acute disseminated encephalomyelitis.

OBJECTIVE: To identify predictors of epilepsy and clinical relapses in children presenting with acute disseminated encephalomyelitis (ADEM). METHODS: Children presenting with ADEM between 2005 and 2017 and tested clinically for MOG-Ab were identified from three tertiary paediatric neurology centres in the United Kingdom. Patients were followed up for a median of 6 years (range, 1-16 years). RESULTS: A total of 74 children were studied (38 females; median age at first presentation: 4.5 years (range, 1.4-16 years)). MOG-Ab was positive in 50/74 (67.6%) of cases, and 27 (54%) of MOG-Ab positive children presented with a neurological relapse over time. MOG-Ab was more frequently positive in the relapsing group than in the monophasic group (27/31 vs 23/43; odds ratio 5.9 (95% CI: 1.8-19.7); p = 0.002). 16/74 (22%) children had seizures during the acute presentation with ADEM and 12/74 (16.2%) patients were diagnosed with post-ADEM epilepsy. The diagnosis of post-ADEM epilepsy was more frequently observed in children with relapsing disease than monophasic disease (10/31 vs 2/43; odds ratio 9.8 (95% confidence interval (CI): 2.0-48.7); p = 0.003), in children who had positive intrathecal oligoclonal bands than those with negative bands (4/7 vs 4/30; odds ratio 8.7 (95% CI: 1.4-54.0); p = 0.027) and in children who had positive MOG-Ab than negative MOG-Ab cases (11/12 vs 39/62; odds ratio 6.5 (95% CI:0.8-53.6); p = 0.051). CONCLUSION: A higher relapse rate and a greater risk of post-ADEM epilepsy in children with MOG-Ab-associated disease may indicate a chronic disease with immune-mediated seizures in these children.

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.

Atypical Pediatric Demyelinating Diseases of the Central Nervous System.

PURPOSE OF REVIEW: Pediatric central nervous system demyelinating diseases include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and acute disseminated encephalomyelitis (ADEM). As diagnostic criteria become more inclusive, the risk of misdiagnosis of atypical demyelinating diseases of rheumatologic, infectious, and autoimmune etiology increases. RECENT FINDINGS: We review mimics of multiple sclerosis, neuromyelitis optica spectrum disorder, and acute disseminated encephalomyelitis, including rheumatologic diseases: systemic lupus erythematosus and neuro-Behçet disease; infectious diseases: human immunodeficiency virus, progressive multifocal leukoencephalopathy, and subacute sclerosis panencephalitis; and autoimmune diseases including X-linked Charcot-Marie-Tooth disease, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) and autoimmune glial fibrillary acidic protein (GFAP) encephalopathy. Atypical demyelinating disease may mimic classic neuroinflammatory diseases of the central nervous system. Imaging may meet criteria for a diagnosis of multiple sclerosis, or patients may present with optic neuritis and transverse myelitis consistent with neuromyelitis optica spectrum or myelin oligodendrocyte glycoprotein (MOG) antibody disorders. Through careful history-taking and review of atypical MRI findings, we may avoid misdiagnosis and mistreatment.

Isolated seizures during the first episode of relapsing myelin oligodendrocyte glycoprotein antibody-associated demyelination in children.

Myelin oligodendrocyte glycoprotein (MOG) antibodies have a strong association with acute disseminated encephalomyelitis (ADEM) in children, and bilateral and recurrent optic neuritis in children and adults. Recent reports suggest that seizures and encephalopathy may occur in children and adults with MOG antibody-associated disease. We describe the clinical, laboratory, and radiological course of four MOG antibody-positive children who first presented with isolated seizures without fulfilling clinical or radiological criteria for ADEM or other central nervous system demyelination syndromes, who months to years later developed more typical demyelination. This case series highlights a novel observation that isolated seizures in the absence of ADEM may be the index presentation for MOG antibody-associated disease, which should therefore be considered a form of autoimmune epilepsy. It would be reasonable to test for MOG antibodies in children with seizures accompanied by subtle inflammatory changes on magnetic resonance imaging or cerebrospinal fluid analyses, particularly if followed by demyelination, given the clinical and therapeutic implications of an expedited diagnosis in minimizing long-term disability. WHAT THIS PAPER ADDS: Isolated seizures in the absence of acute disseminated encephalomyelitis may be the index presentation for myelin oligodendrocyte glycoprotein antibody-associated demyelination.

CONVULSIONES AISLADAS DURANTE UNA PRIMERA RECAÍDA DE UN EVENTO DESMIELINIZANTE ASOCIADA A ANTICUERPOS CONTRA LA GLICOPROTEINA DE LOS OLIGODENDROCITOS DE LA MIELINA: Los anticuerpos contra la Glicoproteina de los Oligodendrocitos de la Mielina (MOG) están fuertemente asociados con la Encefalomielitis Aguda Diseminada (EMAD) en niños, y con la Neuritis Óptica bilateral recurrente en niños y adultos. Recientes reportes sugieren que convulsiones y encefalopatía pueden presentarse con enfermedad asociada a anticuerpos MOG. Describimos la evolución clínica, serologica y radiológica de cuatro niños con anticuerpos positivos para MOG cuya primera presentación fueron convulsiones aisladas sin cumplir todos los criterios cínicos ni radiológicos para EMAD u otro síndrome desmielinizante del sistema nervioso central; y, que luego de meses a años, desarrollaron una desmielinización típica. Esta serie de casos resalta una nueva observación, en la cual, convulsiones aisladas en ausencia de EMAD puede ser la presentación de enfermedad asociada a anticuerpos para MOG; y, por lo tanto, debe ser considerada una forma de epilepsia autoinmune. Sería razonable buscar anticuerpos para MOG en aquellos niños con convulsiones que se acompañan de cambios inflamatorios sutiles en la resonancia magnética y análisis de líquido cefalorraquídeo, en particular, en aquellos que posteriormente desarrollan desmielinización teniendo en cuenta las implicancias clínicas y terapéuticas de realizar un diagnóstico rápido con el fin de minimizar la discapacidad a largo plazo.

CONVULSÕES ISOLADAS DURANTE O PRIMEIRO EPISÓDIO DE DESMIELINIZAÇÃO ASSOCIADA AO ANTICORPO DE GLICOPROTEÍNA DE OLIGODENDRÓCITO DA MIELINA EM CRIANÇAS: Anticorpos de glicoproteína de oligodendrócito da mielina (GOM) têm forte associação com encefalomielite aguda disseminada (EMAD) em crianças, e com neurite óptica bilateral e recorrente em crianças e adultos. Relatos recentes sugerem que convulsões e encefalopatia podem ocorrer em adultos e crianças com doença associada aos anticorpos GOM. Descrevemos o curso clínico, laboratorial, e radiológico de crianças com anticorpos GOM positivos que apresentaram convulsões isoladas pela primeira vez, sem preencher os critérios clínicos e radiológicos para EMAD ou para outras síndromes desmielinizantes do sistema nervoso central, que nos meses ou anos seguintes desenvolveram desmielinização mais típica. Esta série de casos realça uma nova observação de que convulsões isoladas na ausência de EMAD podem ser sinal de doença relacionada ao anticorpo GOM, e deve portanto ser considerada uma forma de epilepsia auto-imune. Seria razoável testar anticorpos GOM em crianças com convulsões acompanhada de doenças inflamatórias sutis à ressonância magnética ou na análise do fluido cérebro-espinhal, particularmente se seguida por desmielinização, dadas as implicações clínicas e terapêuticas do diagnóstico rápido em minimizar incapacidades no longo prazo.

Pediatric Multiple Sclerosis: an Update.

PURPOSE OF REVIEW: Diagnostic criteria for pediatric-onset multiple sclerosis (POMS) and related demyelinating disorders have been updated, neuroimaging studies have revealed new insights, biological assays identify patients with specific antibodies that influence both diagnosis and treatment, clinical trials are informing on treatment efficacy and safety, and longitudinal studies of neurological, cognitive and quality of life outcomes are informing on the impact of these diseases. We provide updates to assist providers caring for these children. RECENT FINDINGS: The recent 2017 McDonald Criteria for MS provide a simplified means to confirm diagnosis at onset and over time, and have been shown to be equally applicable for POMS. MRI analyses demonstrate that brain volume is reduced at onset, and that both volumetric and tissue integrity measures decline over time, indicating that POMS shares the degenerative aspects that also characterize adult-onset disease. The presence of myelin oligodendrocyte glycoprotein (MOG) antibodies at onset is detected in more than 50% of children with acute disseminated encephalomyelitis. When persistent over time, they are associated with relapsing disease. The first randomized clinical trials of disease supports superiority of fingolimod over subcutaneous interferon beta 1a, and demonstrated a favorable safety profile. Finally, while Expanded Disability Status Scale (EDSS) scores remain low in the first 10 years post-onset, POMS is associated with high rates of patient-reported fatigue and reduced engagement in exercise and carries a risk for cognitive impairment. The past 15 years have borne witness to a marked expansion in recognition and research in POMS. There are now more specific diagnostic criteria, antibodies to CNS proteins appear to define diagnostically distinct disorders, clinical trials have successfully launched and one has completed, and we are gaining increasing appreciation of the impact of MS and related disorders on the lived experience of children and adolescents.

MOG Spectrum Disorders and Role of MOG-Antibodies in Clinical Practice.

Myelin oligodendrocyte glycoprotein (MOG) antibodies (abs) are present in one third of all children with an acute demyelinating syndrome (ADS). MOG-abs can be found in acute disseminated encephalomyelitis (ADEM), transverse myelitis, isolated optic neuritis (ON), or recurrent demyelinating diseases, such as multiphasic neuromyelitis optica spectrum disorders (NMOSD) without aquaporin-4 (AQP4) abs or multiphasic ADEM (MDEM), but rarely in children who subsequently develop multiple sclerosis (MS). The presence of MOG-abs is age dependent with the highest seropositivity rates found in young children and an episode of ADEM, whereas older children with MOG-abs present with ON, myelitis, or brainstem symptoms. MOG-abs, initially thought to be associated with a benign disease course, are found in a substantial proportion of children with relapsing episodes associated with high and persisting MOG-ab titers. This review describes, in particular, the increasing spectrum of phenotypes associated with MOG-abs with a focus on clinical characteristics, radiological features, and therapeutic aspects.

'Leukodystrophy-like' phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease.

AIM: To review the demographics and clinical and paraclinical parameters of children with myelin oligodendrocyte glycoprotein (MOG) antibody-associated relapsing disease. METHOD: In this UK-based, multicentre study, 31 children with MOG antibody-associated relapsing disease were studied retrospectively. RESULTS: Of the 31 children studied, 14 presented with acute disseminated encephalomyelitis (ADEM); they were younger (mean 4.1y) than the remainder (mean 8.5y) who presented with optic neuritis and/or transverse myelitis (p<0.001). Similarly, children who had an abnormal brain magnetic resonance imaging (MRI) at onset (n=20) were younger than patients with normal MRI at onset (p=0.001) or at follow-up (p<0.001). 'Leukodystrophy-like' MRI patterns of confluent largely symmetrical lesions was seen during the course of the disease in 7 out of 14 children with a diagnosis of ADEM, and was only seen in children younger than 7 years of age. Their disability after a 3-year follow-up was mild to moderate, and most patients continued to relapse, despite disease-modifying treatments. INTERPRETATION: MOG antibody should be tested in children presenting with relapsing neurological disorders associated with confluent, bilateral white matter changes, and distinct enhancement pattern. Children with MOG antibody-associated disease present with age-related differences in phenotypes, with a severe leukoencephalopathy phenotype in the very young and normal intracranial MRI in the older children. This finding suggests a susceptibility of the very young and myelinating brain to MOG antibody-mediated mechanisms of damage. WHAT THIS PAPER ADDS: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination manifest with an age-related phenotype. Children with MOG antibody and 'leukodystrophy-like' imaging patterns tend to have poor response to second-line immunotherapy.

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.

Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein.

The role of autoantibodies in the pathogenesis of multiple sclerosis (MS) and other demyelinating diseases is controversial, in part because widely used western blotting and ELISA methods either do not permit the detection of conformation-sensitive antibodies or do not distinguish them from conformation-independent antibodies. We developed a sensitive assay based on self-assembling radiolabeled tetramers that allows discrimination of antibodies against folded or denatured myelin oligodendrocyte glycoprotein (MOG) by selective unfolding of the antigen domain. The tetramer radioimmunoassay (RIA) was more sensitive for MOG autoantibody detection than other methodologies, including monomer-based RIA, ELISA or fluorescent-activated cell sorting (FACS). Autoantibodies from individuals with acute disseminated encephalomyelitis (ADEM) selectively bound the folded MOG tetramer, whereas sera from mice with experimental autoimmune encephalomyelitis induced with MOG peptide immunoprecipitated only the unfolded tetramer. MOG-specific autoantibodies were identified in a subset of ADEM but only rarely in adult-onset MS cases, indicating that MOG is a more prominent target antigen in ADEM than MS.

Persistent presence of the anti-myelin oligodendrocyte glycoprotein autoantibody in a pediatric case of acute disseminated encephalomyelitis followed by optic neuritis.

We report the case of a 5-year-old Japanese girl who initially had acute disseminated encephalomyelitis (ADEM) and was positive for the myelin oligodendrocyte glycoprotein (MOG) antibodies and developed unilateral optic neuritis (ON) 71 days after ADEM onset. The patient's serum was positive for the anti-MOG antibodies from the onset of ADEM to the development of ON. This phenotype has been reported in only two previous articles, and the specific mechanism of action of the anti-MOG antibodies is not yet understood. Our case suggests that the anti-MOG antibody can be associated with the pathogenesis of ADEM followed by ON. Thus, patients with ADEM who test positive for the anti-MOG antibody may be at risk of developing subsequent ON.

Blood parameters in pediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.

BACKGROUND AND OBJECTIVES: Patients with myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) clinically present e.g. with acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis (TM) or aquaporin-4-IgG (AQP4-IgG) negative neuromyelitis optica spectrum disorders (NMOSD)-like phenotypes. We aimed to analyze and compare blood parameters in children with MOGAD, AQP4-IgG-positive NMOSD (hence NMOSD), multiple sclerosis (MS) and healthy controls (HC). METHODS: We evaluated differences in complete blood counts (CBC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and C-reactive protein (CRP) between these four groups and within the groups between clinical attack, acute treatment and remission. RESULTS: Our cohort consisted of 174 children and adolescents with a total of 550 timepoints: 66 patients had MOGAD (202 timepoints), 11 NMOSD (76 timepoints), 58 MS (219 timepoints) and 39 were HC (53 timepoints). At clinical attack, leukocyte counts were elevated in MOGAD compared to remission (p < 0.001) and compared to all other groups (p < 0.001). NLR was high in MOGAD and NMOSD, and PLR was high in NMOSD, however, after correction for multiple testing these findings did not remain significant. While glucocorticoids caused an increase of leukocyte counts and NLR in NMOSD and MS, these values remained stable during acute treatment in MOGAD. In remission, NLR normalized in MOGAD, while it stayed high in NMOSD. PLR increased in NMOSD and was significantly higher compared to all other groups. DISCUSSION: Some blood parameters, mainly leukocyte and differential counts, might help clinicians to evaluate disease activity, differentiate relapses from pseudo-relapses and even distinguish between different disease entities.

Patterns and utility of myelin oligodendrocyte glycoprotein (MOG) antibody testing in cerebrospinal fluid.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an idiopathic central nervous system (CNS) demyelinating disease gaining recognition with wider availability of cell-based assay (CBA) testing and recently published diagnostic criteria. However, uncertainty remains regarding the interpretation of antibody titers, particularly cerebrospinal fluid (CSF) MOG antibody titers. METHODS: All MOG IgG CBA results performed by the provincial MitogenDx laboratory in Alberta from July 2017 to July 2023 were retrieved. Chart review was performed in patients with both serum and CSF testing and ≥ 1 positive MOG antibody result. Demographics, antibody titers, clinical and imaging features, treatment, and diagnosis were analyzed based on serum/CSF status. RESULTS: Among 4494 MOG CBA assays, there were 413 CSF samples in 402 patients, and 268 patients had at least one associated serum sample. Mean time between CSF and serum testing was 20.9 days (range 0-870 days), most with testing within 30 days. Five of the 268 patients had serum positive/CSF positive MOG antibodies, 4 with acute disseminated encephalomyelitis and 1 with longitudinally extensive transverse myelitis. Twenty-three patients had serum positive/CSF negative MOG and 13/23 with optic neuritis. CSF MOG antibody positive patients were younger, and more likely to remain MOG seropositive versus CSF negative patients. No seronegative patient had MOG antibodies in CSF. CONCLUSIONS: In province-wide testing, CSF MOG antibodies were rare, only in MOG seropositive patients and none with optic neuritis. Our study does not support a clear role for CSF MOG antibody testing in the majority of patients, although further study is required.

Cerebrospinal fluid eosinophils in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: Eosinophils in cerebrospinal fluid (CSF) are an uncommon finding most often associated with parasitic infections, but have also been described in some neuroinflammatory disorders. Eosinophilic infiltration is not thought to be a typical feature of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). We aim to describe the rate of CSF eosinophil positivity in a cohort of pediatric MOGAD patients. METHODS: Single-center retrospective chart review of pediatric MOGAD patients. Clinical and laboratory data was collected from the electronic medical record and analyzed. RESULTS: Of 46 pediatric patients with positive serum myelin oligodendrocyte glycoprotein antibody (MOG-IgG) identified, 38 patients fulfilling internationally proposed MOGAD diagnostic criteria were included for analysis. 6 patients with MOGAD were excluded as no CSF data was available, and 2 patients with positive MOG-IgG but diagnosis more consistent with MS were excluded. Median age was 7.3 years, and 19/38 (50 %) were female. Acute disseminated encephalomyelitis (ADEM) was the most common presenting phenotype (23/38, 61 %), and other phenotypes included optic neuritis (10/38, 26 %), transverse myelitis (3/38, 8 %), and neuromyelitis optica spectrum disorder (NMOSD) (2/38, 5 %). 12 of 36 (33 %) patients with all lumbar puncture (LP) data available had CSF eosinophils present, with eosinophil mean of 3 % and range from 1 % to 18 % of CSF while blood cells. CONCLUSION: CSF eosinophils were present in one third of pediatric MOGAD patients, which is a higher rate than previously reported in either MOGAD or aquaporin-4 antibody positive NMOSD cohorts. Understanding the CSF composition of pediatric MOGAD patients helps to facilitate more prompt diagnosis and treatment and may shed light onto underlying pathologic mechanisms of disease with the goal to inform future therapeutic targets.

Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases.

Recent studies demonstrated the presence of autoantibodies to native myelin oligodendrocyte glycoprotein (MOG) in juvenile patients with acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS). However, so far no longitudinal studies on anti-MOG antibodies have been performed. Therefore, we determined serum and CSF antibodies against native human MOG in 266 pediatric and adult subjects with ADEM, clinically isolated syndrome (CIS), MS, other neurological diseases (OND) and healthy controls (HC) and longitudinal samples of 25 patients with ADEM, CIS, MS and OND using an immunofluorescence assay. We detected serum high-titer MOG IgG in 15/34 (44%) patients with ADEM, but only rarely in CIS (3/38, 8%), MS (2/89, 2%), OND (1/58, 2%) and HC (0/47). Longitudinal analysis of serum anti-MOG IgG showed different temporal dynamics of serum antibody responses in ADEM, CIS and MS and indicated an association of a favorable clinical outcome in ADEM with a decrease in antibody titers over time.

Spectrum of anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated diseases: an Indian perspective.

Myelin oligodendrocyte glycoprotein antibody (MOG-Ab) is involved in the pathogenesis of central nervous system (CNS) demyelination disorders. We aimed to explore the spectrum of MOG-Ab-associated diseases in eastern India. A single-center, prospective observational study was done over a period of 2 years in a tertiary care hospital of eastern India. Patients with CNS demyelination disorders who tested positive for MOG-Ab using live cell-based assay were included in the study; while, those with age less than 1 year, documented preexisting CNS structural lesions, developmental delays or diagnosed multiple sclerosis were excluded. Demographic profile, clinical spectrum, disease course, radiological features as well as response to treatment were analyzed among included patients. Twenty MOG-Ab-positive patients were included (M:F 1:1.85). The median age of symptom onset was 10.5 years. The median follow-up of patients was 13 months. Acute disseminated encephalomyelitis (ADEM) was the commonest presentation at first attack (55%), followed by optic neuritis (ON) (45%). Patients with ADEM had a significantly lower age at first attack (p = 0.025). Monophasic and relapsing disease courses were seen in 45% and 55% patients, respectively. While all patients with only ADEM had a monophasic course, 77.8% with ON had a relapsing course. Among patients who presented with isolated transverse myelitis, 75% had a monophasic course and all had disease confined to the spinal cord. Good response to corticosteroids was seen in majority of participants. Second-line drugs were needed in 55% patients, rituximab being the commonest second-line agent used. 35% patients had significant disability (EDSS > 4) at last follow-up. MOG-Ab-associated diseases have diverse clinical phenotypes characterized by age-dependent pattern-specific courses.

COVID-19-associated Acute Disseminated Encephalomyelitis-like Disease in 2 Children.

BACKGROUND: The coronavirus disease 2019 pandemic was caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the predominant clinical presentation is a respiratory disease, neurologic manifestations are being recognized increasingly. CASE REPORT: We report 2 children 9 years of age who developed acute disseminated encephalomyelitis-like disease associated with SARS-CoV-2. Seizures and encephalopathy were the main central nervous system symptoms. The cerebrospinal fluid analysis performed within the first week of disease onset showed elevated protein in both children with normal cell count and no evidence of infection including negative SARS-CoV-2 by antibody and polymerase chain reaction. Brain magnetic resonance imaging revealed T2A, fluid-attenuated inversion recovery cortical and subcortical hyperintensity without restricted diffusion consistent with acute disseminated encephalomyelitis-like disease. They received methylprednisolone followed by therapeutic plasma exchange. One of them showed complete clinical improvement and resolution in magnetic resonance imaging findings. The other developed laminar necrosis in brain magnetic resonance imaging and showed significant clinical improvement after therapeutic plasma exchange. He was positive for positive SARS-CoV-2 antibody in cerebrospinal fluid on day 55 of admission. They were both positive for SARS-CoV-2 antibodies in serum after 2 weeks. CONCLUSIONS: Our two cases highlight the occurrence of acute disseminated encephalomyelitis-like disease as a postinfectious/immune-mediated complication of SARS-CoV-2 infection.

Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease.

OBJECTIVE: Myelin oligodendrocyte glycoprotein (MOG) is a candidate target antigen in demyelinating diseases of the central nervous system (CNS). Although MOG is encephalitogenic in different animal models, the relevance of this antigen in human autoimmune diseases of the CNS is still controversial. METHODS: We investigated the occurrence and biological activity of antibodies to native MOG (nMOG) in 47 children during a first episode of CNS demyelination (acute disseminated encephalomyelitis [ADEM], n = 19 and clinical isolated syndrome [CIS], n = 28) by a cell-based bioassay. RESULTS: High serum immunoglobulin G (IgG) titers to nMOG were detected in 40% of children with CIS/ADEM but 0% of the control children affected by other neurological diseases, healthy children, or adults with inflammatory demyelinating diseases, respectively. By contrast, IgM antibodies to nMOG occurred in only 3 children affected by ADEM. Children with high anti-nMOG IgG titer were significantly younger than those with low IgG titer. Anti-nMOG IgG titers did not differ between the ADEM and CIS group, and did not predict conversion from CIS to MS during a mean 2-year follow-up. However, intrathecal IgG anti-MOG antibody synthesis was only seen in CIS children. IgG antibodies to nMOG not only bound to the extracellular domain of nMOG, but also induced natural killer cell-mediated killing of nMOG-expressing cells in vitro. INTERPRETATION: Overall, these findings suggest nMOG as a major target of the humoral immune response in a subgroup of children affected by inflammatory demyelinating diseases of the CNS. Children may provide valuable insight into the earliest immune mechanisms of CNS demyelination.

[Acute disseminated encephalomyelitis in childhood]. / Akut disszeminált encephalomyelitis gyermekkorban.

BACKGROUND AND PURPOSE: Acute disseminated encephalomyelitis is a rare inflammatory demyelinating disorder often preceded by infection or vaccination. The purpose of the study was the systematic analysis of clinical, radiological and microbiological profiles of children treated at Szent László Hospital, and the comparison of findings with literature data. METHODS: Demographic, infectological, clinical, radiological, laboratory and virological data of patients treated and followed-up between 1-Jan-1998 and 30-June-2008 were reviewed and analysed. RESULTS: 19 children met diagnostic criteria. Their mean age was 6.8 years. A prodromal illness--mostly febrile viral infection, upper respiratory infection or chickenpox--preceded neurological symptoms in 17 patients. All had polysymptomatic encephalopathy, 2 children had spinal symptoms. The cerebrospinal fluid was abnormal in all but one. A viral etiology was definite in 7 and probable in 8 cases. MRI disclosed white matter changes in 18, cortical and deep gray matter in 16, cerebellar in 6, brain stem in 14 and spinal cord changes in 2 cases. Repeat MRI performed mean 4 months later showed complete resolution in 6 and partial resolution in 11 patients. 13 patients received high-dose methylprednisolone, 2 of whom were also treated with plasma exchange and 1 with immunoglobulin. 9 children required mechanical ventilation. 2 patients died, 10 recovered without and 7 with sequelae. 2 patients developed further demyelinating events: multiple sclerosis and multiphasic disseminated encephalomyelitis, respectively. CONCLUSION: Clinical, radiological and follow-up results were similar to those published in literature however, triggering viruses were identified in a larger proportion of cases.

Ratio of Alpha 2-Macroglobulin Levels in Cerebrospinal Fluid and Serum: An Expression of Neuroinflammation in Acute Disseminated Encephalomyelitis.

BACKGROUND: Acute encephalitis and encephalopathy are life-threatening diseases in children. However, no laboratory examinations are performed for their early diagnosis and treatment. Alpha 2-macroglobulin (α2M) is a blood glycoprotein that increases during the early stages of inflammation. In the present study, we investigated the role of α2M levels in acute encephalitis and encephalopathy. METHODS: We analyzed the cerebrospinal fluid and serum samples from patients with acute disseminated encephalomyelitis, infection-related acute encephalopathy, febrile status epilepticus, and febrile seizure simplex type. Samples were collected from the pediatric department of hospitals throughout the Fukushima Prefecture between January 1, 1999, and May 31, 2012. RESULTS: α2M levels in the cerebrospinal fluid were 4.7 (3.8-8.4) µg/mL for acute disseminated encephalomyelitis, 2.1 (1.1-2.3) µg/mL for infection-related acute encephalopathy, 1.1 (0.9-6.4) µg/mL for febrile status epilepticus, and 1.0 (0.8-1.1) µg/mL for febrile seizure simplex type. α2M levels in patients with acute disseminated encephalomyelitis were significantly higher than those in patients with infection-related acute encephalopathy and febrile seizure simplex type (P = 0.019 and P = 0.002, respectively). The ratio of α2M level in the cerebrospinal fluid to that in the serum in patients with acute disseminated encephalomyelitis was significantly higher than the ratio in patients with febrile status epilepticus (P = 0.04). In patients with acute disseminated encephalomyelitis, α2M levels in the cerebrospinal fluid decreased with treatment. CONCLUSIONS: Our results suggest that α2M levels in the cerebrospinal fluid reflect the neuroinflammatory status of patients with acute disseminated encephalomyelitis.

[Clinical and biochemical characteristics of atypical variants of multiple sclerosis]. / Kliniko-biokhimicheskie kharakteristiki atipichnykh variantov rasseiannogo skleroza.

AIM: To study the clinical and biochemical features of atypical variants of multiple sclerosis (MS) (tumefactive demyelination (TD), Balo's concentric sclerosis (BCS)) and acute disseminated encephalomyelitis (ADEM)). MATERIAL AND METHODS: Forty-two patients were studied, including 32 patients with atypical variants of MS (6 patients with BCS and 26 patients with TD) and 10 patients with ADEM. The control group included 20 healthy volunteers. Clinical characteristics and EDSS scores were evaluated. Antibodies to aquaporin 1 (AQP1-IgG), aquaporin 4 (AQP4-IgG), antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) and aquaporin 1 (AQP1) in serum and cerebrospinal fluid (CSF) were detected using ELISA. RESULTS AND CONCLUSION: BCS and TD occurred both in isolation and comorbid with MS (in 50% of cases with BCS, 50% of cases with TD). Atypical symptoms of MS were detected in 50% of cases of CFS, 15.4% of cases of PD. The levels of CSF cytosis and CSF protein were not significantly different between the groups. The levels of AQP1-IgG, AQP4-IgG, AQP1, MOG-IgG in serum with BCS, TD and ADEM were significantly higher than in the control group. No significant differences were found between atypical variants of MS. A correlation between a high level of MOG-IgG and the EDSS score in BCS was shown. MOG-IgG may have a pathogenetic significance in BCS. Further studies of AQP1-IgG, AQP4-IgG and MOG-IgG in patients with atypical variants of MS are needed.