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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.

Objective To report the clinical and investigative features of children with a clinical diagnosis of probable autoimmune encephalopathy, both with and without antibodies to central nervous system antigens. Method Patients with encephalopathy plus one or more of neuropsychiatric symptoms, seizures, movement disorder or cognitive dysfunction, were identified from 111 paediatric serum samples referred from five tertiary paediatric neurology centres to Oxford for antibody testing in 2007–2010. A blinded clinical review panel identified 48 patients with a diagnosis of probable autoimmune encephalitis whose features are described. All samples were tested/retested for antibodies to N-methyl-D-aspartate receptor (NMDAR), VGKC-complex, LGI1, CASPR2 and contactin-2, GlyR, D1R, D2R, AMPAR, GABA(B)R and glutamic acid decarboxylase. Results Seizures (83%), behavioural change (63%), confusion (50%), movement disorder (38%) and hallucinations (25%) were common. 52% required intensive care support for seizure control or profound encephalopathy. An acute infective organism (15%) or abnormal cerebrospinal fluid (32%), EEG (70%) or MRI (37%) abnormalities were found. One 14-year-old girl had an ovarian teratoma. Serum antibodies were detected in 21/48 (44%) patients: NMDAR 13/48 (27%), VGKC-complex 7/48(15%) and GlyR 1/48(2%). Antibody negative patients shared similar clinical features to those who had specific antibodies detected. 18/34 patients (52%) who received immunotherapy made a complete recovery compared to 4/14 (28%) who were not treated; reductions in modified Rankin Scale for children scores were more common following immunotherapies. Antibody status did not appear to influence the treatment effect. Conclusions Our study outlines the common clinical and paraclinical features of children and adolescents with probable autoimmune encephalopathies. These patients, irrespective of positivity for the known antibody targets, appeared to benefit from immunotherapies and further antibody targets may be defined in the future.

BackgroundLesion 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).ObjectiveWe aimed to evaluate brain MRI changes over time in paediatric MOGAD.MethodsRetrospective 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.Results200 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).ConclusionsThese 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.

Myasthenia gravis (MG) is an antibody-mediated disorder of the neuromuscular junction affecting children and adults. MG is a treatable condition with most patients requiring immunosuppression for disease control and/or remission. Juvenile myasthenia gravis (JMG) is rare in comparison with adult-onset MG but given the same underlying pathophysiology, treatment strategies are similar to those in adults. Until recently, there were only a few randomised controlled trials (RCTs) for MG treatments in adults and none in children, and management strategies were primarily based on expert consensus. In addition, treatment options for refractory MG cases have been severely limited, resulting in poor long-term quality of life in such patients due to the significant disease burden. Recently, there have been several RCTs focussing on novel therapeutic strategies with potentially promising outcomes, suggesting a change in MG management over the coming years and access to more effective and faster-acting drugs for MG patients. This paper will review current and new MG treatments including efgartigimod, eculizumab, rozanolixizumab, ravulizumab, and zilucoplan, with a focus on juvenile myasthenia gravis.

ObjectiveTo describe onset clinical features predicting time to first relapse and time to long-term visual, motor and cognitive disabilities in paediatric-onset aquaporin-4 antibody (AQP4-IgG) neuromyelitis optica spectrum disorders (NMOSDs).MethodsIn this retrospective UK multicentre cohort study, we recorded clinical data of paediatric-onset AQP4-IgG NMOSD. Univariate and exploratory multivariable Cox proportional hazard models were used to identify long-term predictors of permanent visual disability, Expanded Disability Status Scale (EDSS) score of 4 and cognitive impairment.ResultsWe included 49 paediatric-onset AQP4-IgG patients (38.8% white, 34.7% black, 20.4% Asians and 6.1% mixed), mean onset age of 12±4.1 years, and 87.7% were female. Multifocal onset presentation occurred in 26.5% of patients, and optic nerve (47%), area postrema/brainstem (48.9%) and encephalon (28.6%) were the most involved areas. Overall, 52.3% of children had their first relapse within 1 year from disease onset. Children with onset age <12 years were more likely to have an earlier first relapse (p=0.030), despite showing no difference in time to immunosuppression compared with those aged 12–18 years at onset. At the cohort median disease duration of 79 months, 34.3% had developed permanent visual disability, 20.7% EDSS score 4 and 25.8% cognitive impairment. Visual disability was associated with white race (p=0.032) and optic neuritis presentations (p=0.002). Cognitive impairment was predicted by cerebral syndrome presentations (p=0.048), particularly if resistant to steroids (p=0.034).ConclusionsAge at onset, race, onset symptoms and resistance to acute therapy at onset attack predict first relapse and long-term disabilities. The recognition of these predictors may help to power future paediatric clinical trials and to direct early therapeutic decisions in AQP4-IgG NMOSD.

AimTo investigate the epidemiology, clinical profile and risk factors of pseudotumor cerebri syndrome (PTCS) in children aged 1–16 years.MethodsA national prospective population-based cohort study over 25 months. Newly diagnosed PTCS cases notified via British Paediatric Surveillance Unit were ascertained using classical diagnostic criteria and categorised according to 2013 revised diagnostic criteria. We derived national age, sex and weight-specific annual incidence rates and assessed effects of sex and weight categories.ResultsWe identified 185 PTCS cases of which 166 also fulfilled revised diagnostic criteria. The national annual incidence (95% CI) of PTCS in children aged 1–16 years was 0.71 (0.57 to 0.87) per 100 000 population increasing with age and weight to 4.18 and 10.7 per 100 000 in obese boys and girls aged 12–15 years, respectively. Incidence rates under 7 years were similar in both sexes. From 7 years onwards, the incidence in girls was double that in boys, but only in overweight (including obese) children. In children aged 12–15 years, an estimated 82% of the incidence of PTCS was attributable to obesity. Two subgroups of PTCS were apparent: 168 (91%) cases aged from 7 years frequently presented on medication and with headache and were predominantly female and obese. The remaining 17 (9%) cases under 7 years often lacked these risk factors and commonly presented with paralytic squint.ConclusionsThis uniquely large population-based study of childhood PTCS will inform the design of future intervention studies. It suggests that weight reduction is central to the prevention of PTCS.

Background Neuromyelitis Optica (NMO) is a severe and rare inflammatory condition, where relapses are predictive of disability. Methods We describe a national paediatric NMO cohort's clinical, MRI, outcome, and prognostic features in relation to Aquaporin-4 antibody (AQP4-Ab) status, and compared to a non NMO control cohort. Observations Twenty NMO cases (females=90%; AQP4-Ab positive=60%; median age=10.5yrs) with median follow-up=6.1yrs were compared to a national cohort sample of known sequential AQP4-Ab negative first episode CNS acquired demyelination cases (n=29; females=55%; all AQP4-Ab negative; median age=13.6yrs). At presentation, 40% NMO cases had unilateral optic neuritis (ON); 20% bilateral ON; 15% transverse myelitis (TM); 15% simultaneous TM 10% Acute disseminated encephalomyelitis. At follow up, 55% had a clinical demyelinating episode involving the brain; 30% of cases had abnormal brain MRI at onset and 75% by follow up. NMO brain scan lesions compared to controls were large (>2 cm), acute lesions largely resolved on repeat imaging, and often showed T1 hypointense lesions. Mean time to relapse=0.76yrs (95% CI 0.43–1.1yrs) for AQP4-Ab positive vs 2.4yrs in AQP4-Ab negative cases (95% CI 1.1–3.6yrs). In AQP4-Ab positive cases, 10/12 had visual acuity<6/60 Snellen in ≥1 eye (0/8 AQP4-Ab negative), and 3 AQP4-Ab negative cases were wheelchair-dependent. Conclusions In children, NMO is associated with early recurrence and visual impairment in AQP4-Ab positivity and physical disability in AP4-Ab negative relapsing cases. Distinct MRI changes appear more commonly and earlier compared to adult NMO. Early AQP4-Ab testing may allow prompt immunomodulatory treatment to minimise disability.

Objective: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time. Methods: We conducted a population active surveillance study. All paediatricians, and ophthalmologists (n = 4095) were sent monthly reporting cards (September 2009–September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review. Results: Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3–15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years (n = 63) was 1.52:1 (p = 0.045). The incidence of first onset ADS in children aged 1–15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18–11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria. Conclusions: We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design.

Lysosomal storage disorders (LSDs) are genetically inherited diseases characterized by the accumulation of disease-specific biological materials such as proteolipids or metabolic intermediates within the lysosome. The lysosomal compartment’s central importance to normal cellular function can be appreciated by examining the various pathologies that arise in LSDs. These disorders are invariably fatal, and many display profound neurological impairment that begins in childhood. However, recent studies have revealed that several LSDs also have irregularities in the function of the immune system. Gaucher disease, mucopolysaccharidosis VII, and α-mannosidosis are examples of a subset of LSD patients that are predisposed towards immune suppression. In contrast, GM2 gangliosidosis, globoid cell leukodystrophy, Niemann-Pick disease type C1 and juvenile neuronal ceroid lipofuscinosis are LSDs that are predisposed towards immune system hyperactivity. Antigen presentation and processing by dedicated antigen presenting cells (APCs), secretion of pore-forming perforins by cytotoxic-T lymphocytes, and release of pro-inflammatory mediators by mast cells are among the many crucial immune system functions in which the lysosome plays a central role. Although the relationship between the modification of the lysosomal compartment in LSDs and modulation of the immune system remains unknown, there is emerging evidence for early neuroimmune responses in a variety of LSDs. In this review we bridge biochemical studies on the lysosomal compartment’s role in the immune system with clinical data on immune system irregularities in a subset of LSDs.