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Arterial ischaemic stroke is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood arterial ischaemic stroke have been undertaken. We aimed to investigate the epidemiology and clinical features of childhood arterial ischaemic stroke in a population-based cohort. Children aged 29 days to less than 16 years with radiologically confirmed arterial ischaemic stroke occurring over a 1-year period (July 1, 2008, to June 30, 2009) residing in southern England (population denominator 5·99 million children) were eligible for inclusion. Cases were identified using several sources (paediatric neurologists and trainees, the British Paediatric Neurology Surveillance Unit, paediatricians, radiologists, physiotherapists, neurosurgeons, parents, and the Paediatric Intensive Care Audit Network). Cases were confirmed by personal examination of cases and case notes. Details of presenting features, risk factors, and investigations for risk factors were recorded by analysis of case notes. Capture–recapture analysis was used to estimate completeness of ascertainment. We identified 96 cases of arterial ischaemic stroke. The crude incidence of childhood arterial ischaemic stroke was 1·60 per 100 000 per year (95% CI 1·30–1·96). Capture–recapture analysis suggested that case ascertainment was 89% (95% CI 77–97) complete. The incidence of arterial ischaemic stroke was highest in children aged under 1 year (4·14 per 100 000 per year, 95% CI 2·36–6·72). There was no difference in the risk of arterial ischaemic stroke between sexes (crude incidence 1·60 per 100 000 per year [95% CI 1·18–2·12] for boys and 1·61 per 100 000 per year [1·18–2·14] for girls). Asian (relative risk 2·14, 95% CI 1·11–3·85; p=0·017) and black (2·28, 1·00–4·60; p=0·034) children were at higher risk of arterial ischaemic stroke than were white children. 82 (85%) children had focal features (most commonly hemiparesis) at presentation. Seizures were more common in younger children (≤1 year) and headache was more common in older children (>5 years; p<0·0001). At least one risk factor for childhood arterial ischaemic stroke was identified in 80 (83%) cases. Age and racial group, but not sex, affected the risk of arterial ischaemic stroke in children. Investigation of such differences might provide causative insights. The Stroke Association, UK.

Background: There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope. Objective: The purpose of this review is to revise the 2007 definitions in order to incorporate advances in delineating the clinical and neuroradiologic features of these disorders. Methods: Through a consensus process, in which input was sought from the 150 members of the Study Group, criteria were drafted, revised and finalized. Final approval was sought through a web survey. Results: Revised criteria are proposed for pediatric acute disseminated encephalomyelitis, pediatric clinically isolated syndrome, pediatric neuromyelitis optica and pediatric MS. These criteria were approved by 93% or more of the 56 Study Group members who responded to the final survey. Conclusions: These definitions are proposed for clinical and research purposes. Their utility will depend on the outcomes of their application in prospective research.

Objective N-methyl-D-aspartate receptor antibody (NMDAR-Ab) encephalitis is a well-recognised clinico-immunological syndrome that presents with neuropsychiatric symptoms cognitive decline, movement disorder and seizures. This study reports the clinical features, management and neurological outcomes of paediatric NMDAR-Ab-mediated neurological disease in the UK. Design A prospective surveillance study. Children with NMDAR-Ab-mediated neurological diseases were voluntarily reported to the British Neurological Surveillance Unit (BPNSU) from November 2010 to December 2011. Initial and follow-up questionnaires were sent out to physicians. Results Thirty-one children fulfilled the criteria for the study. Eight presented during the study period giving an incidence of 0.85 per million children per year (95% CI 0.64 to 1.06); 23 cases were historical. Behavioural change and neuropsychiatric features were present in 90% of patients, and seizures and movement disorders both in 67%. Typical NMDAR-Ab encephalitis was reported in 24 children and partial phenotype without encephalopathy in seven, including predominantly psychiatric (four) and movement disorder (three). All patients received steroids, 22 (71%) received intravenous immunoglobulin, 9 (29%) received plasma exchange,and 10 (32%) received second-line immunotherapy. Of the 23 patients who were diagnosed early, 18 (78%) made a full recovery compared with only 1 of 8 (13%) of the late diagnosed patients (p=0.002, Fisher's exact test). Seven patients relapsed, with four needing additional second-line immunotherapy. Conclusions Paediatric NMDAR-Ab-mediated neurological disease appears to be similar to adult NMDAR-Ab encephalitis, but some presented with a partial phenotype. Early treatment was associated with a quick and often full recovery.

To evaluate the prevalence and predictors of vitamin D insufficiency (VDI) in children in Great Britain. A nationally representative cross-sectional study survey of children (1102) aged 4-18 years (999 white, 570 male) living in private households (January 1997-1998). Interventions provided information about dietary habits, physical activity, socio-demographics, and blood sample. Outcome measures were vitamin D insufficiency (<50 nmol/L). Vitamin D levels (mean = 62.1 nmol/L, 95%CI 60.4-63.7) were insufficient in 35%, and decreased with age in both sexes (p<0.001). Young People living between 53-59 degrees latitude had lower levels (compared with 50-53 degrees, p = 0.045). Dietary intake and gender had no effect on vitamin D status. A logistic regression model showed increased risk of VDI in the following: adolescents (14-18 years old), odds ratio (OR) = 3.6 (95%CI 1.8-7.2) compared with younger children (4-8 years); non white children (OR = 37 [95%CI 15-90]); blood levels taken December-May (OR = 6.5 [95%CI 4.3-10.1]); on income support (OR = 2.2 [95%CI 1.3-3.9]); not taking vitamin D supplementation (OR = 3.7 [95%CI 1.4-9.8]); being overweight (OR 1.6 [95%CI 1.0-2.5]); <1/2 hour outdoor exercise/day/week (OR = 1.5 [95%CI 1.0-2.3]); watched >2.5 hours of TV/day/week (OR = 1.6[95%CI 1.0-2.4]). We confirm a previously under-recognised risk of VDI in adolescents. The marked higher risk for VDI in non-white children suggests they should be targeted in any preventative strategies. The association of higher risk of VDI among children who exercised less outdoors, watched more TV and were overweight highlights potentially modifiable risk factors. Clearer guidelines and an increased awareness especially in adolescents are needed, as there are no recommendations for vitamin D supplementation in older children.

Magnetic resonance imaging (MRI) biomarkers are vital for multiple sclerosis (MS) clinical research and trials but quantifying them requires multi-contrast protocols and limits the use of abundant single-contrast hospital archives. We developed MindGlide, a deep learning model to extract brain region and white matter lesion volumes from any single MRI contrast. We trained MindGlide on 4247 brain MRI scans from 2934 MS patients across 592 scanners, and externally validated it using 14,952 scans from 1,001 patients in two clinical trials (primary-progressive MS and secondary-progressive MS trials) and a routine-care MS dataset. The model outperformed two state-of-the-art models when tested against expert-labelled lesion volumes. In clinical trials, MindGlide detected treatment effects on T2-lesion accrual and cortical and deep grey matter volume loss. In routine-care data, T2-lesion volume increased with moderate-efficacy treatment but remained stable with high-efficacy treatment. MindGlide uniquely enables quantitative analysis of archival single-contrast MRIs, unlocking insights from untapped hospital datasets. Here, the authors develop an AI tool called MindGlide that can extract key information from brain images acquired as part of the routine care of multiple-sclerosis patients to help interpret treatment effects, which previously required manual analysis.

Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor. In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80–320 μg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP. Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease. cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit. German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.

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.

Paediatric relapsing demyelinating syndromes of the CNS define a group of diseases that have different phenotypes. Although for some of them, such as multiple sclerosis and neuromyelitis optica spectrum disorder (NMOSD), diagnostic criteria have been developed, diagnostic uncertainties are not uncommon. We aimed to identify the key features that unify phenotypes, and focused on patients with myelin oligodendrocyte glycoprotein (MOG) antibodies, to investigate whether they show distinctive clinical and radiological features, independently of their original diagnosis. We then generated a diagnostic algorithm for clinical use. We reviewed the clinical characteristics, MOG and AQP4 antibodies, intrathecal oligoclonal bands, and Epstein-Barr virus serology results of 110 children with relapsing demyelinating syndromes. A neuroradiologist, masked to the diagnosis, scored the MRI scans. Clinical, radiological, and serological test results were compared between the different relapsing demyelinating syndromes. 62 children (56%) were diagnosed with multiple sclerosis, 27 (25%) with NMOSD, 14 (13%) with multiphasic disseminated encephalomyelitis (MDEM), and 7 (6%) with relapsing idiopathic optic neuritis (RION). Paediatric multiple sclerosis and NMOSD with AQP4 antibodies showed radiological and serological features typical of the respective adult phenotypes. Eight children with NMOSD (30%) were positive for AQP4 antibodies. MOG antibodies were found in 16 (83%) of 19 NMOSD patients without AQP4 antibodies, in all 14 children with MDEM, and in two with RION (33%). Children with MOG antibodies were younger, less likely to present with area postrema syndrome, had lower disability, longer time to relapse, and more cerebellar peduncle lesions than those with AQP4 antibody-positive NMOSD (all p<0·05). A diagnostic algorithm, applicable to any episode of CNS demyelination, led to four main relapsing demyelinating syndromes: multiple sclerosis, NMOSD with APQ4 antibodies, MOG-antibody-associated disease, and antibody-negative relapsing demyelinating syndrome. Using an integrative approach of clinical phenotyping, radiological analysis, and MOG and AQP4 antibodies, we were able to delineate patients to different disease phenotypes—namely, multiple sclerosis, MOG antibody spectrum disorder, and AQP4 antibody spectrum disorder. Although the clinical presentation can overlap (eg, optic neuritis and transverse myelitis) the pathogenic mechanisms are likely to be different. A correct diagnosis in children with non-multiple sclerosis phenotypes has both treatment and prognostic implications. National Institute for Health Research.

Wilson disease (WD) is a rare, recessively inherited disorder of copper metabolism mainly affecting liver and brain. In childhood, it is known to have a predominant hepatic phenotype. It is likely that the low awareness for WD-associated neuropsychiatric signs and symptoms in this age group means that neurological Wilson’s disease is underdiagnosed in children and young people. Practitioners should be alert for this complication in children with or without liver disease. Management of children with WD requires a dedicated multidisciplinary approach involving hepatologists, geneticists, neurologists and psychiatrists to ensure subtle neuropsychiatric symptoms are identified early and addressed appropriately. This review highlights recent advances in hepatic and neuropsychiatric symptoms of WD in childhood, specific diagnostic tools and pitfalls and summarises existing and potential future treatment options.

ObjectiveWe aim to share our experiences with an Adult Neurology audience of five children (3F, 2M) with Hemophagocytic Lymphohistiocytosis (HLH), who presented with an atypical neuroinflammatory disorder.MethodsSingle institution retrospective case seriesResultsMean age of presentation was 6 years (3–11). Presenting features were headache (N=1), optic neuritis (N=1), diplopia (N=2) and hemiplegia (N=1).4 children had MRI imaging suggestive of demyelination. One child had an isolated area of restricted diffusion in the brainstem. An initial working diagnosis of ‘CLIPPERS’ (Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) was made in three cases. Only two children ever met the criteria for systemic HLH. Pathogenic variants of RAB27A, STXBP2, UNC13 and PRF1 were separately identified in four children which are all associated with familial Hemophagocytic Lymphohis- tiocytosis (fHLH). Four children in this series have already undergone successful Haemopoietic Stem Cell Transplantation (HSCT).ConclusionsWe propose that adult neurologists consider genetic panel and immunological (Natural Killer Cell function, perforin expression and granulocyte release assay) testing for HLH in cases of atypical recurrent CNS inflammation and presentations consistent with ‘CLIPPERS’. Clinical management may be changed as HSCT is considered the gold standard treatment for familial HLH. Nonetheless, the long term history of these cases and risk of recurrent CNS inflammation post HSCT remains unclear.a.parida@nhs.net