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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.

The association of recognisable neurological conditions with an underlying malignancy is well described. In this review we explore the complex interplay of genetic, environmental and tumour factors which contribute to autoimmunity and paraneoplastic conditions. We review the current understanding of the pathogenesis of well recognised paraneoplastic conditions in children including Opsoclonus myoclonus ataxia syndrome, N-Methyl-D Aspartate receptor encephalitis and limbic encephalitis, and the broad approaches to treatment. Rapid advances in oncological treatment has expanded the arsenal of therapeutic modalities. We explore the broad spectrum of immune therapies in childhood cancer, and the potential neurological complications of these novel therapies, and discuss the fine balance of risk and benefit that these bring., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare with regards to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)

Narcolepsy with cataplexy and myasthenia gravis are both chronic neurologic conditions causing symptoms of muscle weakness, often affecting facial muscles, and have both been attributed to an immune-mediated etiology. We report an adolescent girl diagnosed with both conditions and discuss possible shared mechanisms and the diagnostic challenges presented by her case to inform and aid clinicians managing children and young people with these rare conditions.

Background: Lesion resolution is often observed in children with myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and asymptomatic lesions are less commonly reported in MOGAD than in multiple sclerosis (MS)., Objective: We aimed to evaluate brain MRI changes over time in paediatric MOGAD., Methods: Retrospective study in eight UK paediatric neuroscience centres. Acute brain MRI and available follow-up MRIs were reviewed. Predictors for lesion dynamic were evaluated using multivariable regression and Kaplan-Meier survival analyses were used to predict risk of relapse, disability and MOG-Ab status., Results: 200 children were included (MOGAD 97; MS 103). At first MRI post attack, new symptomatic and asymptomatic lesions were seen more often in MS versus MOGAD (52/103 vs 28/97; p=0.002 and 37/103 vs 11/97; p<0.001); 83% of patients with MOGAD showed at least one lesion's resolution at first follow-up scan, and 23% had normal MRI. Only 1 patient with MS had single lesion resolution; none had normal MRI. Disappearing lesions in MOGAD were seen in 40% after the second attack, 21% after third attack and none after the fourth attack.New lesions at first follow-up scan were associated with increased likelihood of relapse (p=0.02) and persistent MOG-Ab serostatus (p=0.0016) compared with those with no new lesions. Plasma exchange was associated with increased likelihood of lesion resolution (p=0.01). Longer time from symptom onset to steroids was associated with increased likelihood of new lesions; 50% increase at 20 days (p=0.01)., Conclusions: These striking differences in lesion dynamics between MOGAD and MS suggest greater potential to repair. Early treatment with steroids and plasma exchange is associated with reduced likelihood of new lesions., Competing Interests: Competing interests: OA-m receives funding from the Association British Neurologists, MS Society and the Berkeley Foundation’s AW Pidgley Memorial Trust. RF has received grant funding from the NIHR Efficacy and Mechanism Evaluation Programme. CH has received educational and travel grants from Merck Serono and Bayer and Biogen. ML receives research grants from Action Medical Research, the DES society, GOSH charity, National Institute for Health Research, MS Society, and SPARKS charity; receives research support grants from the London Clinical Research Network and Evelina Appeal; has received consultation fees from CSL Behring, Novartis and Octapharma; received travel grants from Merck Serono. OC is a member of independent DSMB for Novartis, gave a teaching talk on McDonald criteria in a Merck local symposium, and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)

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.

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.

Aim: To determine whether a pH probe or multichannel intraluminal impedance (MII) more frequently detected gastro-oesophageal reflux and test the hypothesis that acid reflux was associated with lower baseline impedance., Methods: A prospective study of infants in whom reflux was suspected and evaluated using combined pH and multichannel impedance. Studies were considered abnormal if the acid index was >10% or there were >79MII reflux events in 24 hours. The acid index was the percentage of total study time with a pH

Studies of adult patients have demonstrated that weekend admissions compared with weekday admissions had a significantly higher hospital mortality rate. We have reviewed the literature to determine if the timing of admission, for example, weekend or weekday, influenced mortality and morbidity in children. Seventeen studies reported the effect of timing of admission on mortality, and only four studies demonstrated an increase in those admitted at the weekend. Meta-analysis of the results of 15 of the studies demonstrated there was no significant weekend effect. There was, however, considerable heterogeneity in the studies. There were two large UK studies: one reported an increased mortality only for planned weekend admissions likely explained by planned admissions for complex conditions and the other showed no significant weekend effect. Two studies, one of which was large (n=2913), reported more surgical complications in infants undergoing weekend oesophageal atresia and trachea-oesophageal repair. Medication errors have also been reported to be more common at weekends. Five studies reported the effect of length of stay, meta-analysis demonstrated a significantly increased length of stay following a weekend admission, the mean difference was approximately 1 day. Those data, however, should be interpreted with the caveat that there was no adjustment in all of the studies for differences in disease severity. We conclude that weekend admission overall does not increase mortality but may be associated with a longer length of stay and, in certain conditions, with greater morbidity., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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.)

Aim: In 2004, wide variation in the investigation and management of gastro-oesophageal reflux (GOR) of infants on UK major neonatal units was demonstrated. Our aim was to resurvey neonatal practitioners to determine current practice and whether it was now evidence based., Methods: A questionnaire was sent to all 207 UK neonatal units., Results: Responses were obtained from 84% of units. The most frequent 'investigation' was a trial of therapy (83% of units); pH studies were used in 38%, upper GI contrast studies in 19% and multichannel intraluminal impedance (MII)/pH studies in 5%. Only six units suggested a threshold for an abnormal pH study and two units for an abnormal MII study. Infants were commenced on antireflux medication without investigation always in 32% of units, often in 29%, occasionally in 19% and only never in 1%. Gaviscon was used as first line treatment in 60% of units, and other medications included ranitidine in 53%, thickening agents in 27%, proton pump inhibitors in 23%, domperidone in 22% and erythromycin in 6%., Conclusion: There remains a wide variation in diagnostic and treatment strategies for infants with suspected GOR on neonatal intensive care units, emphasising the need for randomised trials to determine appropriate GOR management., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Type 1 narcolepsy (NT1) is a chronic primary disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disrupted nocturnal sleep. NT1 is linked to hypothalamic hypocretin deficiency, strongly associated with Human Leukocyte Antigen (HLA) marker DQB1*06:02 and of probable autoimmune origin. NT1 is usually associated with increased rates of overweight and obesity, and sometimes with increases in overnight blood pressure and increased rates of hypoventilation with raised CO 2 levels overnight. Many of these are predisposing factors for pseudotumor cerebri syndrome (PTCS). We present a case of a young girl with both NT1 and PTCS that responded well to treatment with acetazolamide after early identification, with improvement of headache and resolution of hypoventilation., (Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Gastro-oesophageal reflux (GOR) and apnoea are common in infants; whether there is a causal relationship is controversial., Objectives: To determine whether there was a temporal relationship between GOR and apnoea, in particular, the frequency of obstructive apnoeas and if the frequency of GOR episodes correlated with apnoea frequency when maturity at testing was taken into account., Methods: Polysomnography and pH/multichannel intraluminal impedance (MII) studies were performed. Apnoeas were classified as central, obstructive, or mixed. MII events were classified as acidic (pH <4) or weakly acidic (4 < pH < 7). Apnoea frequency in the 5-min period after a reflux event was compared to that in the 5-min period preceding the event and that in a 5-min reflux-free period (control period)., Results: Forty infants (median gestational age 29 [range 24-42] weeks) were assessed at a post-conceptional age of 37 (30-54) weeks. Obstructive (n = 580), central (n = 900), and mixed (n = 452) apnoeas were identified; 381 acid reflux events were detected by MII and 153 by the pH probe only. Apnoeas were not more frequent following GOR than during control periods. Both the frequency of apnoeas (p = 0.002) and GOR episodes (p = 0.01) were inversely related to post-conceptional age at testing, but were not significantly correlated with each other when controlled for post-conceptional age., Conclusions: These results suggest that GOR does not cause apnoea., (© 2017 S. Karger AG, Basel.)

Oxygenation impairment can be assessed non-invasively by determining the degree of right-to-left shunt and ventilation/perfusion (V A /Q) inequality. These indices have been used in sick newborn infants, but normative values have not been reported which are essential to determine the magnitude of the abnormality. We, therefore, aimed to measure the shunt and V A /Q in infants with no history of respiratory conditions and determine if there was any effect of supine or prone position and the reproducibility of the data. Data were analysed from infants who had undergone a hypoxic challenge and in a subset who had been assessed in the supine or prone position. Transcutaneous oxygen saturations (SpO 2 ) were recorded at fractions of inspired oxygen (F I O 2 ) of 0.21 and 0.15. Two independent raters used a computer software algorithm which analysed and fitted paired data for F I O 2 and SpO 2 and derived a curve which represented the best fit for each infant's data and calculated the shunt and V A /Q. The raters ability to interpret the SpO 2 value which corresponded to a given F I O 2 was compared. The downwards displacement of the F I O 2 versus SpO 2 curve was used to estimate the degree of right-to-left shunt and the rightwards shift of the curve was used to calculate the V A /Q ratio. The mean (SD) gestational age of the 145 infants was 39 (1.6) weeks, their birth weight was 2990 (578) gms and median (range) postnatal age at measurement 3 (1-8) days. The mean (SD) V A /Q ratio was 0.95 (0.21). None of the infants had a right-to-left shunt. No significant differences were found in V A /Q in the supine compared to the prone position. The intraclass correlation coefficient of V A /Q between two independent raters was 0.968 (95% CI 0.947-0.980), p < 0.001. Right-to-left shunt and V A /Q ratio in healthy newborn infants were similar in the prone compared to the supine position.

The ventilatory response of infants of mothers who smoke and misuse substances and controls to carbon dioxide was assessed at 6-12 weeks and the perinatal period. Infants of mothers who smoke and misuse substances had a dampened response at the peak age of sudden infant death syndrome, greater than in the perinatal period., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Infants of smoking (S) and substance misusing (SM) mothers have an increased risk of sudden infant death syndrome. The aim of this study was to test the hypothesis that infants of SM or S mothers compared with infants of non-SM, non-smoking mothers (controls) would have a poorer ventilatory response to hypoxia, which was particularly marked in the SM infants., Design: Physiological study., Setting: Tertiary perinatal centre., Patients: 21 SM; 21 S and 19 control infants. Infants were assessed before maternity/neonatal unit discharge., Interventions: Maternal and infant urine samples were tested for cotinine, cannabinoids, opiates, amphetamines, methadone, cocaine and benzodiazepines., Main Outcome Measures: During quiet sleep, the infants were switched from breathing room air to 15% oxygen and changes in minute volume were assessed., Results: The SM infants had a greater mean increase (p=0.028, p=0.034, respectively) and a greater magnitude of decline (p<0.001, p=0.018, respectively) in minute volume than the S infants and the controls. The rate of decline in minute volume was greater in the SM infants (p=0.008) and the S infants (p=0.011) compared with the controls., Conclusions: Antenatal substance misuse and smoking affect the infant's ventilatory response to a hypoxic challenge., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Pulmonary hypertension (PH) is a common finding in infants with bronchopulmonary dysplasia (BPD). The aim of this review is to describe recent advances in the diagnosis and treatment of PH and discuss whether they will benefit infants and children with BPD related PH. Echocardiography remains the mainstay of diagnosis but has limitations, further developments in diagnostic techniques and identification of biomarkers are required. There are many potential therapies for PH associated with BPD. Inhaled nitric oxide has been shown to improve short term outcomes only. Sidenafil in resource limited settings was shown in three randomized trials to significantly reduce mortality. The efficacy of other therapies including prostacyclin, PDE3 inhibitors and endothelin receptor blockers has only been reported in case reports or case series. Randomized controlled trials with long term follow up are required to appropriately assess the efficacy of therapies aimed at improving the outcome of children with PH.

Unlabelled: Congenital central hypoventilation syndrome (CCHS) is characterised by hypoventilation most marked during sleep and is often associated with abnormalities of the autonomic nervous system. We report an infant with severe CCHS and Hirschsprung disease in whom, while awaiting genotyping, the diagnosis was facilitated by the results of a carbon dioxide (CO2) sensitivity study in the neonatal period and was confirmed by paired-like homeobox 2B (PHOX2B) mutational analysis. The infant had no ventilatory response to increased inspired carbon dioxide levels when either awake or asleep suggesting he had a severe form for CCHS; indeed, he subsequently demonstrated to have the 20/31 genotype. This is the first case report of a genotype-confirmed CCHS disease in a neonate with Hirschsprung disease further characterised by a ventilatory challenge., Conclusion: CO2 sensitivity status may assist in determining the severity of the CCHS.