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Background and Objectives: Antibodies to myelin oligodendrocyte glycoprotein (MOG-Ab) have recently been reported in patients with encephalitis who do not fulfill criteria for acute disseminated encephalomyelitis (ADEM). We evaluated a cohort of these children and compared them with children with ADEM., Methods: This retrospective, multicenter cohort study comprised consecutive patients <18 years of age with MOG-Ab who fulfilled criteria for autoimmune encephalitis. These patients were stratified into (1) children not fulfilling criteria for ADEM (encephalitis phenotype) and (2) children with ADEM. Clinical/paraclinical data were extracted from the electronic records. Comparisons were made using the Mann-Whitney U test and χ 2 Fisher exact test for statistical analysis., Results: From 235 patients with positive MOG-Ab, we identified 33 (14%) with encephalitis and 74 (31%) with ADEM. The most common presenting symptoms in children with encephalitis were headache (88%), seizures (73%), and fever (67%). Infective meningoencephalitis was the initial diagnosis in 67%. CSF pleocytosis was seen in 79%. Initial MRI brain was normal in 8/33 (24%) patients. When abnormal, multifocal cortical changes were seen in 66% and unilateral cortical changes in 18%. Restricted diffusion was demonstrated in 43%. Intra-attack new lesions were seen in 7/13 (54%). When comparing with children with ADEM, children with encephalitis were older (median 8.9 vs 5.7 years, p = 0.005), were more likely to be admitted to intensive care (14/34 vs 4/74, p < 0.0001), were given steroid later (median 16.6 vs 9.6 days, p = 0.04), and were more likely to be diagnosed with epilepsy at last follow-up (6/33 vs 1/74, p = 0.003)., Discussion: MOG-Ab should be tested in all patients with suspected encephalitis even in the context of initially normal brain MRI. Although exclusion of infections should be part of the diagnostic process of any child with encephalitis, in immunocompetent children, when herpes simplex virus CSF PCR and gram stains are negative, these features do not preclude the diagnosis of immune mediated disease and should not delay initiation of first-line immunosuppression (steroids, IVIG, plasma exchange), even while awaiting the antibody results.

It is unknown if cognition is impaired before clinical onset of paediatric acquired demyelinating syndromes. We conducted a matched cohort study using prospectively collected educational data in multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) patients (n = 60) and controls (pooled n = 449,553). Academic performance at ages 10-11 was impaired in MOGAD (-1.27 adjusted z-score [95% CI: -1.81 to -0.73], P < 0.001) and preclinical MS (-0.40 [-0.80 to -0.0003], P = 0.0498). Moderate/high-efficacy MS treatment was associated with better final academic performance (0.92 [0.28-1.57], P = 0.005). After clinical onset MS patients missed 8.7% of school (controls 2.9%, P < 0.001) and MOGAD patients 11.9% (controls 2.0%, P < 0.001)., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

A neurological deterioration in a child presents a significant worry to the family and often a diagnostic challenge to the clinician. A dysregulated immune response is implicated in a wide and growing spectrum of neurological conditions. In this review we consider the current paradigms in which immune-mediated encephalopathies are considered; the development of paediatric specific diagnostic criteria that facilitate early consideration and treatment of immune-mediated conditions and the limitations and potential developments in diagnostic testing. We consider the expanding phenotype of myelin oligodendrocyte glycoprotein antibody, the spectrum of virus-associated encephalopathy syndromes, and the strategies that have been employed to build an evidence base for the management of these rare conditions. Looking forward we explore the potential for advanced molecular investigations to improve our understanding of immune-mediated encephalitides and guide future treatment strategies. Recently characterized immune-mediated central nervous system disorders include new antibodies causing previously recognized phenotypes. Aggregation of conditions with similar clinical triggers, and characterization of unique imaging features in virus-associated encephalopathy syndromes. Immune treatment iscurrently guided by meta-analysis of individualized patient data and/or multi-national consensus., (© 2023 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Background: Data from the early pandemic revealed that 0.62% of children hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had an acute arterial ischemic stroke (AIS). In a larger cohort from June 2020 to December 2020, we sought to determine whether our initial point estimate was stable as the pandemic continued and to understand radiographic and laboratory data that may clarify mechanisms of pediatric AIS in the setting of SARS-CoV-2., Methods: We surveyed international sites with pediatric stroke expertise to determine numbers of hospitalized SARS-CoV-2 patients <18 years, numbers of incident AIS cases among children (29 days to <18 years), frequency of SARS-CoV-2 testing for children with AIS, and numbers of childhood AIS cases positive for SARS-CoV-2 June 1 to December 31, 2020. Two stroke neurologists with 1 neuroradiologist determined whether SARS-CoV-2 was the main stroke risk factor, contributory, or incidental., Results: Sixty-one centers from 21 countries provided AIS data. Forty-eight centers (78.7%) provided SARS-CoV-2 hospitalization data. SARS-CoV-2 testing was performed in 335/373 acute AIS cases (89.8%) compared with 99/166 (59.6%) in March to May 2020, P <0.0001. Twenty-three of 335 AIS cases tested (6.9%) were positive for SARS-CoV-2 compared with 6/99 tested (6.1%) in March to May 2020, P =0.78. Of the 22 of 23 AIS cases with SARS-CoV-2 in whom we could collect additional data, SARS-CoV-2 was the main stroke risk factor in 6 (3 with arteritis/vasculitis, 3 with focal cerebral arteriopathy), a contributory factor in 13, and incidental in 3. Elevated inflammatory markers were common, occurring in 17 (77.3%). From centers with SARS-CoV-2 hospitalization data, of 7231 pediatric patients hospitalized with SARS-CoV-2, 23 had AIS (0.32%) compared with 6/971 (0.62%) from March to May 2020, P =0.14., Conclusions: The risk of AIS among children hospitalized with SARS-CoV-2 appeared stable compared with our earlier estimate. Among children in whom SARS-CoV-2 was considered the main stroke risk factor, inflammatory arteriopathies were the stroke mechanism.

Background and Objectives: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder of the nervous system that classically presents with a combination of characteristic eye movement disorder and myoclonus, in addition to ataxia, irritability, and sleep disturbance. There is good evidence that OMAS is an immune-mediated condition that may be paraneoplastic in the context of neuroblastoma. This syndrome may be associated with long-term cognitive impairment, yet it remains unclear how this is influenced by disease course and treatment. Treatment is largely predicated on immune suppression, but there is limited evidence to indicate an optimal regimen., Methods: Following an international multiprofessional workshop in 2004, a body of clinicians and scientists comprising the International OMS Study group continued to meet biennially in a joint professionals and family workshop focusing on pediatric OMAS. Seventeen years after publication of the first report, a writing group was convened to provide a clinical update on the definitions and clinical presentation of OMAS, biomarkers and the role of investigations in a child presenting with OMAS, treatment and management strategies including identification and support of long-term sequelae., Results: The clinical criteria for diagnosis were reviewed, with a proposed approach to laboratory and radiologic investigation of a child presenting with possible OMAS. The evidence for an upfront vs escalating treatment regimen was reviewed, and a treatment algorithm proposed to recognize both these approaches. Importantly, recommendations on monitoring of immunotherapy response and longer-term follow-up based on an expert consensus are provided., Discussion: OMAS is a rare neurologic condition that can be associated with poor cognitive outcomes. This report proposes an approach to investigation and treatment of children presenting with OMAS, based on expert international opinion recognizing the limited data available., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objectives: To describe the clinical presentation, investigations, management, and disease course in pediatric autoimmune limbic encephalitis (LE)., Methods: In this retrospective observational study, from the UK Childhood Neuroinflammatory Disease network, we identified children from six tertiary centers with LE <18 years old between 2008 and 2021. Clinical and paraclinical data were retrieved from medical records., Results: Twenty-five children fulfilling LE criteria were identified, with median age of 11 years (IQR 8, 14) and median follow-up of 24 months (IQR 18, 48). All children presented with seizures; 15/25 (60%) were admitted to intensive care. Neuroimaging demonstrated asymmetric mesial temporal changes in 8/25 (32%), and extra-limbic changes with claustrum involvement in 9/25 (38%). None were positive for LGI1/CASPR2 antibodies (Abs), 2/25 were positive for serum anti-NMDAR Abs, and 2/15 positive for anti-Hu Abs; one died from relapsing neuroblastoma. Two children had serum and CSF anti-GAD antibodies. Initial immune therapy included steroids in 23/25 (92%), intravenous immunoglobulin (IVIg) in 14/25 (56%), and plasma exchange in 7/25 (28%). The commonest second-line treatment was rituximab in 15/25 (60%). Median duration of hospital admission was 21 days (IQR 11, 30). At last follow-up, 13/25 (52%) had refractory seizures and 16/25 (64%) had memory impairment. Six children (24%) had modified Rankin Scale (mRS) scores ≥3. There was no significant difference in mRS, or long-term cognitive and epilepsy outcomes in those who received rituximab versus those who did not., Interpretation: A diagnosis of autoimmune LE was associated with significant morbidity and adverse outcomes in this pediatric cohort., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: To compare the real-world effectiveness of newer disease-modifying therapies (DMTs) vs injectables in children with relapsing-remitting multiple sclerosis (RRMS)., Methods: In this retrospective, multicenter study, from the UK Childhood Inflammatory Demyelination Network, we identified children with RRMS receiving DMTs from January 2012 to December 2018. Clinical and paraclinical data were retrieved from the medical records. Annualized relapse rates (ARRs) before and on treatment, time to relapse, time to new MRI lesions, and change in Expanded Disability Status Scale (EDSS) score were calculated., Results: Of 103 children treated with DMTs, followed up for 3.8 years, relapses on treatment were recorded in 53/89 (59.5%) on injectables vs 8/54 (15%) on newer DMTs. The ARR was reduced from 1.9 to 1.1 on injectables ( p < 0.001) vs 1.6 to 0.3 on newer DMTs ( p = 0.002). New MRI lesions occurred in 77/89 (86.5%) of patients on injectables vs 26/54 (47%) on newer DMTs ( p = 0.0001). Children on newer DMTs showed longer time to relapse, time to switch treatment, and time to new radiologic activity than patients on injectables (log-rank p < 0.01). After adjustment for potential confounders, multivariable analysis showed that injectables were associated with 12-fold increased risk of clinical relapse (adjusted hazard ratio [HR] = 12.12, 95% CI = 1.64-89.87, p = 0.015) and a 2-fold increased risk of new radiologic activity (adjusted HR = 2.78, 95% CI = 1.08-7.13, p = 0.034) compared with newer DMTs. At 2 years from treatment initiation, 38/103 (37%) patients had MRI activity in the absence of clinical relapses. The EDSS score did not change during the follow-up, and only 2 patients had cognitive impairment., Conclusion: Newer DMTs were associated with a lower risk of clinical and radiologic relapses in patients compared with injectables. Our study adds weight to the argument for an imminent shift in practice toward the use of newer, more efficacious DMTs in the first instance., Classification of Evidence: This study provides Class IV evidence that newer DMTs (oral or infusions) are superior to injectables (interferon beta/glatiramer acetate) in reducing both clinical relapses and radiologic activity in children with RRMS., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a severe immune-mediated disorder. We aim to report the neurologic features of children with PIMS-TS., Methods: We identified children presenting to a large children's hospital with PIMS-TS from March to June 2020 and performed a retrospective medical note review, identifying clinical and investigative features alongside short-term outcome of children presenting with neurologic symptoms., Results: Seventy-five patients with PIMS-TS were identified, 9 (12%) had neurologic involvement: altered conciseness (3), behavioral changes (3), focal neurology deficits (2), persistent headaches (2), hallucinations (2), excessive sleepiness (1), and new-onset focal seizures (1). Four patients had cranial images abnormalities. At 3-month follow-up, 1 child had died, 1 had hemiparesis, 3 had behavioral changes, and 4 completely recovered. Systemic inflammatory and prothrombotic markers were higher in patients with neurologic involvement (mean highest CRP 267 vs 202 mg/L, p = 0.05; procalcitonin 30.65 vs 13.11 μg/L, p = 0.04; fibrinogen 7.04 vs 6.17 g/L, p = 0.07; d-dimers 19.68 vs 7.35 mg/L, p = 0.005). Among patients with neurologic involvement, these markers were higher in those without full recovery at 3 months (ferritin 2284 vs 283 μg/L, p = 0.05; d-dimers 30.34 vs 6.37 mg/L, p = 0.04). Patients with and without neurologic involvement shared similar risk factors for PIMS-TS (Black, Asian and Minority Ethnic ethnicity 78% vs 70%, obese/overweight 56% vs 42%)., Conclusions: Broad neurologic features were found in 12% patients with PIMS-TS. By 3-month follow-up, half of these surviving children had recovered fully without neurologic impairment. Significantly higher systemic inflammatory markers were identified in children with neurologic involvement and in those who had not recovered fully., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To characterize a cohort of children with epilepsia partialis continua (EPC) and develop a diagnostic algorithm incorporating key differential diagnoses., Methods: Children presenting with EPC to a tertiary pediatric neurology center between 2002 and 2019 were characterized., Results: Fifty-four children fulfilled EPC criteria. Median age at onset was 7 years (range 0.6-15), with median follow-up of 4.3 years (range 0.2-16). The diagnosis was Rasmussen encephalitis (RE) in 30 of 54 (56%), a mitochondrial disorder in 12 of 54 (22.2%), and magnetic resonance imaging (MRI) lesion-positive focal epilepsy in 6 of 54 (11.1%). No diagnosis was made in 5 of 54 (9%). Children with mitochondrial disorders developed EPC earlier; each additional year at presentation reduced the odds of a mitochondrial diagnosis by 26% (P = .02). Preceding developmental concerns (odds ratio [OR] 22, P < .001), no seizures prior to EPC (OR 22, P < .001), bilateral slowing on electroencephalogram (EEG) (OR 26, P < .001), and increased cerebrospinal fluid (CSF) protein level (OR 16) predicted a mitochondrial disorder. Asymmetry or hemiatrophy was evident on MRI at presentation with EPC in 18 of 30 (60%) children with RE, and in the remainder at a median of 6 months (range 3-15) after EPC onset. The first diagnostic test is brain MRI. Hemiatrophy may permit a diagnosis of RE with unilateral clinical and EEG findings. For children in whom a diagnosis of RE cannot be made on first scan but the clinical and radiological presentation resembles RE, repeat imaging every 6 months is recommended to detect progressive unicortical hemiatrophy, and brain biopsy should be considered. Evidence of intrathecal inflammation (oligoclonal bands and raised neopterin) can be supportive. In children with bihemispheric EPC, rapid polymerase gamma testing is recommended and if negative, sequencing mtDNA and whole-exome sequencing on blood-derived DNA should be performed., Significance: Children presenting with EPC due to a mitochondrial disorder show clinical features distinguishing them from RE and structural epilepsies. A diagnostic algorithm for children with EPC will allow targeted investigation and timely diagnosis., (© 2020 International League Against Epilepsy.)

Aim: Our objectives were to evaluate the utility of measuring myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) antibodies (Ab) in clinical practice and describe their associated neurological phenotypes in children., Method: Between 2012 and 2017, 371 children with suspected acquired demyelinating syndromes (ADS) seen in three tertiary centres were tested for MOG-Ab and AQP4-Ab. Medical notes were retrospectively reviewed, and clinical and demographic data compiled. Clinical phenotyping was performed blinded to the antibody results., Results: After review, 237 of the 371 were diagnosed with ADS. Of these, 76 out of 237 (32.1%) were MOG-Ab positive and 14 out of 237 (5.9%) were AQP4-Ab positive. None were positive for both autoantibodies. All 134 patients with non-ADS were negative for MOG-Ab. MOG-Ab were identified in 45 out of 70 (64.3%) patients presenting with acute disseminated encephalomyelitis (ADEM) and in 24 out of 25 patients with relapsing ADEM. Thirty-six out of 75 (48%) MOG-Ab positive patients relapsed. Of the 33 children with neuromyelitis optic spectrum disorder, 14 were AQP4-Ab positive, 13 were MOG-Ab positive, and 6 were seronegative. Of the children with longitudinal samples, 8 out of 13 AQP4-Ab remained positive during the disease course compared to 35 out of 43 MOG-Ab (13/16 monophasic and 22/27 relapsing)., Interpretation: Myelin oligodendrocyte glycoprotein antibodies were identified in a third of children with ADS. Almost half of the MOG-Ab positive children relapsed and the majority of them remained antibody positive over 4-years follow-up., What This Paper Adds: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) are highly specific for acquired demyelinating syndromes (ADS). Myelin oligodendrocyte glycoprotein antibodies are not identified in children with peripheral demyelination or genetic leukodystrophies/hypomyelination. Up to 48% of MOG-Ab ADS paediatric patients relapse, higher than previously thought. Seroconversion to MOG-Ab negative status is infrequent; patients may test MOG-Ab positive at follow-up sampling even when asymptomatic. Myelin oligodendrocyte glycoprotein antibodies status should only be used in conjunction with the clinical information to guide maintenance therapy., (© 2018 Mac Keith Press.)

Aim: To determine whether anticoagulation therapy (ACT) in the treatment of neonatal cerebral sinovenous thrombosis (CSVT) improves outcomes, in the presence or absence of pre-existing intracerebral haemorrhage (ICH)., Method: We searched CENTRAL, MEDLINE, Embase, CINAHL, the Web of Science, and clinical trial databases. We considered data from retrospective and prospective cohort studies, case series, and randomized controlled studies evaluating outcomes of CSVT treated with anticoagulation or no anticoagulation. Studies were included if they involved infants either younger than 28 days of age or younger than 44 weeks postmenstrual age at the time of diagnosis of CSVT in which ACT was considered., Results: Seven non-randomized studies were included in meta-analysis. ACT had no significant effect on mortality before discharge either in the presence or absence of pre-existing ICH, nor on the incidence of extension of pre-existing ICH. ACT was associated with a reduced risk of propagation of thrombus (risk ratio 0.14, 95% confidence interval 0.03-0.72)., Interpretation: There are no randomized trials assessing the safety and efficacy of ACT in the treatment of neonatal CSVT. The results of this meta-analysis would justify a position of equipoise and support the need for well-designed randomized controlled trials of ACT in this population., What This Paper Adds: No randomized studies have evaluated anticoagulation therapy (ACT) in neonatal cerebral sinovenous thrombosis. ACT may reduce thrombus propagation. No evidence of increased morbidity or mortality with ACT was demonstrated. A position of equipoise is justified, supporting the need for placebo-controlled randomized trials., (© 2018 Mac Keith Press.)

Background: Maternal smoking, substance misuse in pregnancy and prone sleeping increase the risk of sudden infant death syndrome (SIDS). We examined the effect of maternal smoking, substance misuse and sleeping position on the newborn response to hypoxia., Methods: Infants born between 36 and 42 weeks of gestational age underwent respiratory monitoring in the prone and supine sleeping position before and during a hypoxic challenge. Minute ventilation (MV) and end-tidal carbon dioxide (ETCO 2 ) levels were assessed., Results: Sixty-three infants were studied: 22 controls, 23 whose mothers smoked and 18 whose mothers substance-misused and smoked. In the supine position, baseline MV was higher and ETCO 2 levels were lower in infants of substance-misusing mothers compared to controls (p = 0.015, p = 0.017, respectively). Infants of substance-misusing mothers had a lower baseline MV and higher ETCO 2 levels in the prone position (p = 0.005, p = 0.004, respectively). When prone, the rate of decline in minute ventilation in response to hypoxia was greater in infants whose mothers substance-misused and smoked compared to controls (p = 0.002) and infants of smoking mothers (p = 0.016)., Conclusion: The altered response to hypoxia in the prone position of infants whose mothers substance-misused and smoked in pregnancy may explain their increased vulnerability to SIDS.

BackgroundWe tested the hypotheses that caffeine therapy would increase the ventilatory response to hypercarbia in infants above the effect of maturation and those with a weaker ventilatory response to hypercarbia would be more likely to subsequently develop apnea that required treatment.MethodsInfants born at less than 34 weeks of gestation underwent a steady-state hypercarbic challenge using 0, 2, and 4% carbon dioxide soon after birth that was repeated at weekly intervals. The results of the initial study were compared between infants who did or did not subsequently develop apnea requiring treatment with caffeine.ResultsTwenty-six infants born at a median gestation of 32 (range 31-33) weeks were assessed. Caffeine administration was associated with an increase in CO 2 sensitivity, and the mean increase was 15.3 (95% CI: 1-30) ml/kg/min/% CO 2 . Fourteen infants subsequently developed apnea treated with caffeine. After controlling for gestational age and birth weight, they had significantly lower carbon dioxide sensitivity at their initial study compared with those who did not require treatment.ConclusionCaffeine administration was associated with an increase in the ventilatory response to hypercarbia. An initial weaker ventilatory response to hypercarbia was associated with the subsequent development of apnea requiring treatment with caffeine.

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., (© 2017 Mac Keith Press.)