Cognitive outcome and its neural correlates after cardiorespiratory arrest in childhood.

Hypoxia-ischaemia (HI) can result in structural brain abnormalities, which in turn can lead to behavioural deficits in various cognitive and motor domains, in both adult and paediatric populations. Cardiorespiratory arrest (CA) is a major cause of hypoxia-ischaemia in adults, but it is relatively rare in infants and children. While the effects of adult CA on brain and cognition have been widely studied, to date, there are no studies examining the neurodevelopmental outcome of children who suffered CA early in life. Here, we studied the long-term outcome of 28 children who suffered early CA (i.e., before age 16). They were compared to a group of control participants (n = 28) matched for age, sex and socio-economic status. The patient group had impairments in the domains of memory, language and academic attainment (measured using standardised tests). Individual scores within the impaired range were most commonly found within the memory domain (79%), followed by academic attainment (50%), and language (36%). The patient group also had reduced whole brain grey matter volume, and reduced volume and fractional anisotropy of the white matter. In addition, lower performance on memory tests was correlated with bilaterally reduced volume of the hippocampi, thalami, and striatum, while lower attainment scores were correlated with bilateral reduction of fractional anisotropy in the superior cerebellar peduncle, the main output tract of the cerebellum. We conclude that patients who suffered early CA are at risk of developing specific cognitive deficits associated with structural brain abnormalities. RESEARCH HIGHLIGHTS: Our data shed light on the long-term outcome and associated neural mechanisms after paediatric hypoxia-ischaemia as a result of cardiorespiratory arrest. Patients had impaired scores on memory, language and academic attainment. Memory impairments were associated with smaller hippocampi, thalami, and striatum. Lower academic attainment correlated with reduced fractional anisotropy of the superior cerebellar peduncle.

Anatomo-functional changes in neural substrates of cognitive memory in developmental amnesia: Insights from automated and manual MRI examinations.

Despite bilateral hippocampal damage dating to perinatal or early-childhood period, and severely-impaired episodic memory that unfolds in later childhood, patients with developmental amnesia continue to exhibit well-developed semantic memory across the developmental trajectory. Detailed information on the extent and focality of brain damage in these patients is needed to hypothesize about the neural substrate that supports their remarkable capacity for encoding and retrieval of semantic memory. In particular, we need to assess whether the residual hippocampal tissue is involved in this preservation, or whether the surrounding cortical areas reorganise to rescue aspects of these critical cognitive memory processes after early injury. We used voxel-based morphometry (VBM) analysis, automatic (FreeSurfer) and manual segmentation to characterize structural changes in the brain of an exceptionally large cohort of 23 patients with developmental amnesia in comparison with 32 control subjects. Both the VBM and the FreeSurfer analyses revealed severe structural alterations in the hippocampus and thalamus of patients with developmental amnesia. Milder damage was found in the amygdala, caudate and parahippocampal gyrus. Manual segmentation demonstrated differences in the degree of atrophy of the hippocampal subregions in patients. The level of atrophy in CA-DG subregions and subicular complex was more than 40% while the atrophy of the uncus was moderate (-23%). Anatomo-functional correlations were observed between the volumes of residual hippocampal subregions in patients and selective aspects of their cognitive performance viz, intelligence, working memory, and verbal and visuospatial recall. Our findings suggest that in patients with developmental amnesia, cognitive processing is compromised as a function of the extent of atrophy in hippocampal subregions, such that the greater the damage, the more likely it is that surrounding cortical areas will be recruited to rescue the putative functions of the damaged subregions. Our findings document for the first time not only the extent, but also the limits of circuit reorganization occurring in the young brain after early bilateral hippocampal damage.

Volume reduction of caudate nucleus is associated with movement coordination deficits in patients with hippocampal atrophy due to perinatal hypoxia-ischaemia.

Acute sentinel hypoxia-ischaemia in neonates can target the hippocampus, mammillary bodies, thalamus, and the basal ganglia. Our previous work with paediatric patients with a history of hypoxia-ischaemia has revealed hippocampal and diencephalic damage that impacts cognitive memory. However, the structural and functional status of other brain regions vulnerable to hypoxia-ischaemia, such as the basal ganglia, has not been investigated in these patients. Furthermore, it is not known whether there are any behavioural sequelae of such damage, especially in patients with no diagnosis of neurological disorder. Based on the established role of the basal ganglia and the thalamus in movement coordination, we studied manual motor function in 20 participants exposed to neonatal hypoxia-ischaemia, and a group of 17 healthy controls of comparable age. The patients' handwriting speed and accuracy was within the normal range (Detailed Assessment of Speed of Handwriting), and their movement adaptation learning (Rotary Pursuit task) was comparable to the control group's performance. However, as a group, patients showed an impairment in the Grooved Pegboard task and a trend for impairment in speed of movement while performing the Rotary Pursuit task, suggesting that some patients have subtle deficits in fine, complex hand movements. Voxel-based morphometry and volumetry showed bilateral reduction in grey matter volume of the thalamus and caudate nucleus. Reduced volumes in the caudate nucleus correlated across patients with performance on the Grooved Pegboard task. In summary, the fine movement coordination deficit affecting the hand and the wrist in patients exposed to early hypoxic-ischaemic brain injury may be related to reduced volumes of the caudate nucleus, and consistent with anecdotal parental reports of clumsiness and coordination difficulties in this cohort.

Is chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) in children the same condition as in adults?

This case series describes three children with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), an inflammatory condition characterized by a relapsing-remitting disease course responsive to steroids. The patients (two males, age 3y and 13y; one female, age 14y) presented with ataxia, dysarthria, and multiple cranial neuropathies. All patients demonstrated bilateral nodular lesions with contrast enhancement in the brainstem and cerebellum on magnetic resonance imaging, and perivascular lymphocytes and macrophages infiltrates on brain biopsies. Despite an initially good response to corticosteroids, all patients eventually became steroid-dependent or -resistant, with frequent relapses on maintenance immunosuppressive therapy. Natalizumab and intravenous immunoglobulin stopped neurological disease progression in Patient 1 but he died at 17 years from respiratory complications. Patient 2 went into remission on infliximab and intravenous methylprednisolone for several months but was then diagnosed with Epstein-Barr virus driven B-cell lymphoma 3 years after symptom onset. Patient 3 failed to respond to treatment and died 4 years after diagnosis. CLIPPERS disease in children is aggressive, with poor response to immunotherapy. Earlier use of newer immunotherapeutic agents such as natalizumab may be beneficial. Potential side effects need to be considered carefully. WHAT THIS PAPER ADDS: Paediatric chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) appears a more severe condition than previously reported in adults. Aggressive treatment before neuroaxonal loss may be required for a better outcome.

¿ES LA INFLAMACIÓN LINFOCÍTICA CRÓNICA CON REALCE PERIVASCULAR PONTINO SENSIBLE A LOS ESTEROIDES (CLIPPERS) EN LOS NIÑOS CON LA MISMA CONDICIÓN QUE EN LOS ADULTOS?: Esta serie de casos describe a tres niños con inflamación linfocítica crónica con realce pontinal perivascular sensible a esteroides (CLIPPERS), una enfermedad inflamatoria caracterizada por un curso de enfermedad recurrente-remitente sensible a los esteroides. Los pacientes (dos varones, edad 3 y 13 años, una mujer, edad 14 años) presentaron ataxia, disartria y neuropatías craneales múltiples. Todos los pacientes demostraron lesiones nodulares bilaterales con realce de contraste en el tallo cerebral y el cerebelo en imágenes de resonancia magnética y linfocitos perivasculares y infiltrados de macrófagos en biopsias cerebrales. A pesar de una respuesta inicialmente buena a los corticosteroides, todos los pacientes finalmente se volvieron dependientes de esteroides o resistentes, con recaídas frecuentes en la terapia inmunosupresora de mantenimiento. El natalizumab y la inmunoglobulina intravenosa suspendieron la progresión de la enfermedad neurológica en el paciente 1, pero falleció a los 17 años por complicaciones respiratorias. El paciente 2 entró en remisión con infliximab y metilprednisolona por vía intravenosa durante varios meses, pero luego se le diagnosticó linfoma de células B dirigido por el virus de Epstein-Barr, 3 años después del inicio de los síntomas. El paciente 3 no respondió al tratamiento y murió 4 años después del diagnóstico. La enfermedad de CLIPPERS en los niños es agresiva, con una respuesta deficiente a la inmunoterapia. El uso previo de agentes inmunoterápicos más nuevos como natalizumab puede ser beneficioso. Los posibles efectos secundarios deben considerarse cuidadosamente.

A INFLAMAÇÃO LINFOCÍTICA CRÔNICA COM REALCE PERIVASCULAR PONTINO RESPONSIVA A ESTERÓIDES (CLIPPERS) É A MESMA CONDIÇÃO EM CRIANÇAS E ADULTOS?: Esta série de casos descreve três crianças com inflamação linfocítica crônica com realce perivascular pontino responsiva a esteróides (CLIPPERS), uma condição inflamatória caracterizada por uma doença com curso remissivo-recidivante responsive a esteróides. Os pacientes (dois meninos, idades 3 e 13 anos; uma menina, idade 14 anos) apresentaram ataxia, disartria, e múltiplas neuropatias craniais. Todos os pacientes demonstraram lesões nodulares bilaterais com realce no tronco cerebral e cerebelo ao exame ne ressonância magnética, e infiltrados perivasculares de linfócitos e macrófagos nas biópsias cerebrais. Apesar de uma resposta inicialmente boa aos corticoesteróides, todos os pacientes eventualmente se tornaram esteróide-dependentes ou resistentes, com frequentes recidivas com manutenção de imunoterapia supressora. Natalizumab e imunoglobulina intravenosa interromperam a progressão neurológica da doença no Paciente 1, mas ele veio a óbito na idade de 17 anos devido a complicações respiratórias. O Paciente 2 entrou em remissão com infliximab e metilprednosolona intravenosa por vários meses, mas foi então diagnosticado com linfoma de células B causado por virus Epstein-Barr 3 anos após o início dos sintomas. O Paciente 3 não respondeu ao tratamento e veio a óbito 4 anos após o diagnóstico. Patient 2 went into remission on infliximab and intravenous methylprednisolone for several months but was then diagnosed with Epstein-Barr virus driven B-cell lymphoma 3 years after symptom onset. Patient 3 failed to respond to treatment and died 4 years after diagnosis. INTERPRETAÇÃO: A doença CLIPPERS em crianças é agressiva, com pouca resposta à imunoterapia. O uso precoce de agentes imunoterapêuticos mais novos como natalizumab pode ser benéfico. Potenciais efeitos colaterais devem ser considerados com cautela.

Long-term prognosis after childhood convulsive status epilepticus: a prospective cohort study.

BACKGROUND: The prognosis of convulsive status epilepticus (CSE), a common childhood medical neurological emergency, is not well characterised. We aimed to investigate the long-term outcomes in a cohort of participants who previously had CSE. METHODS: In this prospective study, we followed up a population-based childhood CSE cohort from north London, UK (the north London convulsive status epilepticus surveillance study cohort; NLSTEPSS). We collected data from structured clinical neurological assessment, neurocognitive assessment (Wechsler Abbreviated Scale of Intelligence), brain MRI, medical records, and structured interviews with participants and their parents to determine neurological outcomes, with adverse outcome defined as presence of one or more of epilepsy (active or in remission), motor disability, intellectual disability, or statement of special educational needs. We applied multiple imputation to address missing data and performed binary logistic regression analyses on complete-case and imputed datasets to investigate sociodemographic and CSE factors associated with adverse outcomes. FINDINGS: Of 203 survivors (90% of inception cohort), 134 (66%) were assessed at a median follow-up of 8·9 years (IQR 8·2-9·5). The cumulative incidence of epilepsy was 24·7% (95% CI 16·2-35·6), with most (89%) emerging within 18 months after CSE. The cumulative incidence of epilepsy was lower in patients with prolonged febrile seizures (14·3%, 6·3-29·4) and survivors of acute symptomatic CSE (13·3%, 3·7-37·9) than in those of remote symptomatic CSE (45·5%, 21·3-72·0) and unclassified CSE (50·0%, 25·4-74·6). One participant (2·9%, 0·5-14·5) in the prolonged febrile seizures group developed temporal lobe epilepsy with mesial temporal sclerosis. The absence of fever at CSE was the only predictor of incident epilepsy (odds ratio [OR] 7·5, 95% CI 2·25-25·1). Motor and intellectual disability was seen predominantly in participants who had idiopathic and cryptogenic CSE (seven [36·8%, 95% CI 19·1-59·0] and 16 [84·2%, 62·4-94·5] of 19, respectively) and remote symptomatic CSE (33 [62·3%, 48·8-74·1] and 40 [75·5%, 62·4-85·1] of 53), and most of these participants had pre-existing disabilities. Pre-existing epilepsy was the only predictor of intellectual disability (OR 8·0, 95% CI 1·1-59·6). 51·5% (95% CI 43·1-59·8) of those followed up had a statement of special educational needs. INTERPRETATION: Childhood CSE is associated with substantial long-term neurological morbidity, but primarily in those who have epilepsy, neurological abnormalities, or both before the episode of CSE. Survivors without neurological abnormalities before CSE have favourable outcomes. FUNDING: BUPA Foundation, The Academy of Medical Sciences, Wellcome Trust, National Institute for Health Research, and Young Epilepsy.

Expanding the Distinctive Neuroimaging Phenotype of ACTA2 Mutations.

BACKGROUND AND PURPOSE: Arg179His mutations in ACTA2 are associated with a distinctive neurovascular phenotype characterized by a straight course of intracranial arteries, absent basal Moyamoya collaterals, dilation of the proximal internal carotid arteries, and occlusive disease of the terminal internal carotid arteries. We now add to the distinctive neuroimaging features in these patients by describing their unique constellation of brain malformative findings that could flag the diagnosis in cases in which targeted cerebrovascular imaging has not been performed. MATERIALS AND METHODS: Neuroimaging studies from 13 patients with heterozygous Arg179His mutations in ACTA2 and 1 patient with pathognomonic clinicoradiologic findings for ACTA2 mutation were retrospectively reviewed. The presence and localization of brain malformations and other abnormal brain MR imaging findings are reported. RESULTS: Characteristics bending and hypoplasia of the anterior corpus callosum, apparent absence of the anterior gyrus cinguli, and radial frontal gyration were present in 100% of the patients; flattening of the pons on the midline and multiple indentations in the lateral surface of the pons were demonstrated in 93% of the patients; and apparent "squeezing" of the cerebral peduncles in 85% of the patients. CONCLUSIONS: Because α-actin is not expressed in the brain parenchyma, only in vascular tissue, we speculate that rather than a true malformative process, these findings represent a deformation of the brain during development related to the mechanical interaction with rigid arteries during the embryogenesis.

The Bone Does Not Predict the Brain in Sturge-Weber Syndrome.

BACKGROUND AND PURPOSE: It has been hypothesized that skull marrow signal alteration may represent an early disease manifestation of Sturge-Weber syndrome before development of its intracranial manifestations. We alternatively hypothesized that intraosseous changes are associated with the overlying port-wine stain rather than the intracranial stigmata of Sturge-Weber syndrome and hence are not a predictor of brain involvement. MATERIALS AND METHODS: MR imaging of children presenting with port-wine stain and/or Sturge-Weber syndrome between 1998 and 2017 was evaluated by 2 pediatric neuroradiologists for marrow signal abnormality and pial angioma and other Sturge-Weber syndrome features: ocular hemangioma, atrophy, and white matter changes (advanced myelination). Groups were divided into port-wine stain-only (without intracranial Sturge-Weber syndrome features) and Sturge-Weber syndrome (the presence of cerebral pial angioma). The χ2 test was performed to evaluate the association between port-wine stain and bone marrow changes and between osseous change and pial angioma. RESULTS: We reviewed 139 cases: 40 with port-wine stain-only and 99 with Sturge-Weber syndrome with pial angioma. Fifteen of 99 cases of Sturge-Weber syndrome had no port-wine stain. In the port-wine stain-only cohort, 78% had ipsilateral bony changes and 17% had no intraosseous changes. In the Sturge-Weber syndrome cohort, 84/99 had associated port-wine stain, 91% (P < .01) had bony changes ipsilateral to the port-wine stain or had no bone changes in the absence of port-wine stain, and 77% (P = .27) had bony changes ipsilateral to a cerebral pial angioma. Eighty percent of patients with Sturge-Weber syndrome who lacked a port-wine stain also lacked marrow changes. Five patients with bilateral port-wine stain and bilateral marrow changes had only a unilateral pial angioma. CONCLUSIONS: Intraosseous marrow changes are strongly associated with facial port-wine stain; no significant association was found between pial angioma and bone marrow changes.

Immunotherapy-responsive childhood neurodegeneration with systemic and central nervous system inflammation.

Subacute neuroregression in association with raised neopterin and overexpression of interferon stimulated genes (ISGs) could indicate a type 1 interferonopathy. Here we describe a novel immunotherapy-responsive, clinico-immunological and imaging phenotype with evidence of innate immune activation. Three children (patient 1: 22-month-old boy; patient 2: 5-year-old girl; patient 3: 4-year-old girl) presented with asymmetric bilateral mixed dystonia and spasticity, regression in language (expressive more than receptive) and bulbar symptoms with no evidence of seizures. Symptoms evolved over several weeks to months. Brain MRI changes mimicked cerebral atrophy, initially asymmetric. CSF revealed raised neopterins. Blood RNA assay showed abnormal overexpression of ISGs and transient raised alanine aminotransferase (ALT). Importantly, all three children were treated with intravenous methylprednisolone and immunoglobulin with significant and sustained improvement in their motor and language function, and normalisation of imaging. Immune-mediated encephalitis can masquerade as subacute neuroregression.

Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy.

OBJECTIVE: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy. METHODS: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system. RESULTS: We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine. CONCLUSIONS: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.

Diagnostic algorithm for relapsing acquired demyelinating syndromes in children.

OBJECTIVE: To establish whether children with relapsing acquired demyelinating syndromes (RDS) and myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) show distinctive clinical and radiologic features and to generate a diagnostic algorithm for the main RDS for clinical use. METHODS: A panel reviewed the clinical characteristics, MOG-Ab and aquaporin-4 (AQP4) Ab, intrathecal oligoclonal bands, and Epstein-Barr virus serology results of 110 children with RDS. A neuroradiologist blinded to the diagnosis scored the MRI scans. Clinical, radiologic, and serologic tests results were compared. RESULTS: The findings showed that 56.4% of children were diagnosed with multiple sclerosis (MS), 25.4% with neuromyelitis optica spectrum disorder (NMOSD), 12.7% with multiphasic disseminated encephalomyelitis (MDEM), and 5.5% with relapsing optic neuritis (RON). Blinded analysis defined baseline MRI as typical of MS in 93.5% of children with MS. Acute disseminated encephalomyelitis presentation was seen only in the non-MS group. Of NMOSD cases, 30.7% were AQP4-Ab positive. MOG-Ab were found in 83.3% of AQP4-Ab-negative NMOSD, 100% of MDEM, and 33.3% of RON. Children with MOG-Ab were younger, were less likely to present with area postrema syndrome, and had lower disability, longer time to relapse, and more cerebellar peduncle lesions than children with AQP4-Ab NMOSD. A diagnostic algorithm applicable to any episode of CNS demyelination leads to 4 main phenotypes: MS, AQP4-Ab NMOSD, MOG-Ab-associated disease, and antibody-negative RDS. CONCLUSIONS: Children with MS and AQP4-Ab NMOSD showed features typical of adult cases. Because MOG-Ab-positive children showed notable and distinctive clinical and MRI features, they were grouped into a unified phenotype (MOG-Ab-associated disease), included in a new diagnostic algorithm.

Melanoma in congenital melanocytic naevi.

Congenital melanocytic naevi (CMN) are a known risk factor for melanoma, with the greatest risk currently thought to be in childhood. There has been controversy over the years about the incidence of melanoma, and therefore over the clinical management of CMN, due partly to the difficulties of histological diagnosis and partly to publishing bias towards cases of malignancy. Large cohort studies have demonstrated that melanoma risk in childhood is related to the severity of the congenital phenotype. New understanding of the genetics of CMN offers the possibility of improvement in diagnosis of melanoma, identification of those at highest risk, and new treatment options. We review the world literature and our centre's experience over the last 25 years, including the molecular characteristics of melanoma in these patients and new melanoma incidence and outcome data from our prospective cohort. Management strategies are proposed for presentation of suspected melanoma of the skin and the central nervous system in patients with CMN, including use of oral mitogen-activated protein kinase kinase inhibitors in NRAS-mutated tumours.

Cerebral Magnetic Resonance Imaging in Children With Prenatal Drug Exposure.

This study aimed to evaluate cerebral magnetic resonance imaging (MRI) scans of children with prenatal drug exposure in a clinical context. A hospital-based cohort of 10- to 14-year-old children, prenatally exposed to alcohol, opioids, and polysubstances, and a group of sex- and age-matched controls were examined with cerebral MRI. Scans obtained from 34 exposed children and 40 controls were scored based on the presence and degree of pathology by an experienced pediatric neuroradiologist blinded to the participants' background. Overall visual detectable MRI pathology was found in 35% of the exposed children and 33% of the controls (odds ratio = 1.08; 95% confidence interval = 0.36-3.25). No specific imaging pattern following prenatal drug exposure was seen by the means of simple visual analysis of cerebral MRI scans. Although cerebral MRI is feasible, it is probably of limited value in the clinical assessment of children with prenatal drug exposure.

Deep sequencing reveals persistence of cell-associated mumps vaccine virus in chronic encephalitis.

Routine childhood vaccination against measles, mumps and rubella has virtually abolished virus-related morbidity and mortality. Notwithstanding this, we describe here devastating neurological complications associated with the detection of live-attenuated mumps virus Jeryl Lynn (MuVJL5) in the brain of a child who had undergone successful allogeneic transplantation for severe combined immunodeficiency (SCID). This is the first confirmed report of MuVJL5 associated with chronic encephalitis and highlights the need to exclude immunodeficient individuals from immunisation with live-attenuated vaccines. The diagnosis was only possible by deep sequencing of the brain biopsy. Sequence comparison of the vaccine batch to the MuVJL5 isolated from brain identified biased hypermutation, particularly in the matrix gene, similar to those found in measles from cases of SSPE. The findings provide unique insights into the pathogenesis of paramyxovirus brain infections.

Hippocampal and diencephalic pathology in developmental amnesia.

Developmental amnesia (DA) is a selective episodic memory disorder associated with hypoxia-induced bilateral hippocampal atrophy of early onset. Despite the systemic impact of hypoxia-ischaemia, the resulting brain damage was previously reported to be largely limited to the hippocampus. However, the thalamus and the mammillary bodies are parts of the hippocampal-diencephalic network and are therefore also at risk of injury following hypoxic-ischaemic events. Here, we report a neuroimaging investigation of diencephalic damage in a group of 18 patients with DA (age range 11-35 years), and an equal number of controls. Importantly, we uncovered a marked degree of atrophy in the mammillary bodies in two thirds of our patients. In addition, as a group, patients had mildly reduced thalamic volumes. The size of the anterior-mid thalamic (AMT) segment was correlated with patients' visual memory performance. Thus, in addition to the hippocampus, the diencephalic structures also appear to play a role in the patients' memory deficit.

Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin-B6-Dependent Epilepsy.

Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B6 vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC, which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. Pre-treatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli mutant lacking the PROSC homolog (ΔYggS) is pyridoxine sensitive; complementation with human PROSC restored growth whereas hPROSC encoding p.Leu175Pro, p.Arg241Gln, and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells, which is how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Although the mechanism involved is not fully understood, our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions.

ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE): protocol for a multicentre randomised controlled trial.

INTRODUCTION: Infectious and immune-mediated encephalitides are important but under-recognised causes of morbidity and mortality in childhood, with a 7% death rate and up to 50% morbidity after prolonged follow-up. There is a theoretical basis for ameliorating the immune response with intravenous immunoglobulin (IVIG), which is supported by empirical evidence of a beneficial response following its use in the treatment of viral and autoimmune encephalitis. In immune-mediated encephalitis, IVIG is often used after a delay (by weeks in some cases), while diagnosis is confirmed. Wider use of IVIG in infectious encephalitis and earlier use in immune-mediated encephalitis could improve outcomes for these conditions. We describe the protocol for the first ever randomised control trial of IVIG treatment for children with all-cause encephalitis. METHODS AND ANALYSIS: 308 children (6 months to 16 years) with a diagnosis of acute/subacute encephalitis will be recruited in ∼30 UK hospitals and randomised to receive 2 doses (1 g/kg/dose) of either IVIG or matching placebo, in addition to standard treatment. Recruitment will be over a 42-month period and follow-up of each participant will be for 12 months post randomisation. The primary outcome is 'good recovery' (score of 2 or lower on the Glasgow Outcome Score Extended-paediatric version), at 12 months after randomisation. Additional secondary neurological measures will be collected at 4-6 weeks after discharge from acute care and at 6 and 12 months after randomisation. Safety, radiological, other autoimmune and tertiary outcomes will also be assessed. ETHICS AND DISSEMINATION: This trial has been approved by the UK National Research Ethics committee (South Central-Oxford A; REC 14/SC/1416). Current protocol: V4.0 (10/03/2016). The findings will be presented at national and international meetings and conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT02308982, EudraCT201400299735 and ISRCTN15791925; Pre-results.