Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.

Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review.

With advances in genetic testing and improved access to such advances, whole exome sequencing is becoming a first-line investigation in clinical work-up of children with developmental delay/intellectual disability (ID). As a result, the need to understand the importance of genetic variants and its effect on the clinical phenotype is increasing. Here, we report on the largest cohort of patients with HNRNPU variants. These 21 patients follow on from the previous study published by Yates et al. in 2017 from our group predominantly identified from the Deciphering Developmental Disorders study that reported seven patients with HNRNPU variants. All the probands reported here have a de novo loss-of-function variant. These probands have craniofacial dysmorphic features, in the majority including widely spaced teeth, microcephaly, high arched eyebrows, and palpebral fissure abnormalities. Many of the patients in the group also have moderate to severe ID and seizures that tend to start in early childhood. This series has allowed us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency, and expand substantially on already published literature on HNRNPU-related neurodevelopmental syndrome.

Surgical management of raised intracranial pressure secondary to otogenic infection and venous sinus thrombosis.

PURPOSE: This study reviews paediatric patients with raised intracranial pressure as a result of venous sinus thrombosis secondary to otogenic mastoiditis, requiring admission to the paediatric neuroscience centre at the University Hospital Wales, Cardiff. The consensus regarding the management of otogenic hydrocephalus in the published literature is inconsistent, with a trend towards conservative over surgical management. We reviewed our management of this condition over a 9-year period especially with regard to ventriculo-peritoneal (VP) shunting. METHODS: Analysis of a prospectively collected database of paediatric surgical patients was analysed and patients diagnosed with otogenic hydrocephalus from November 2010 to August 2018 were identified. Our data was compared with the published literature on this condition. RESULTS: Eleven children, 7 males and 4 females, were diagnosed with otogenic hydrocephalus over the 9-year period. Five (45.5%) required VP shunt insertion to manage their intracranial pressure and protect their vision. The remaining six patients (54.5%) were managed medically. CONCLUSIONS: When children with mastoiditis and venous sinus thrombosis progress to having symptoms or signs of raised intracranial pressure, they should ideally be managed within a neuroscience centre. Of those children, almost half will need permanent cerebrospinal fluid diversion to protect their sight.

Core Health Outcomes in Childhood Epilepsy (CHOICE): Development of a core outcome set using systematic review methods and a Delphi survey consensus.

OBJECTIVE: Establishing a core set of outcomes to be evaluated and reported in intervention trials aims to improve the usefulness of health research. There is no established core outcome set (COS) for childhood epilepsies. The aim of this study was to select a COS to be used in evaluative research of interventions for children with rolandic epilepsy (RE). METHODS: We followed guidance from the COMET (Core Outcome Measures in Effectiveness Trials) Initiative. First, we identified outcomes that had been measured in research through a systematic review. Second, young people with RE, parents, and professionals were invited to take part in a Delphi survey in which participants rated the importance of candidate outcomes. Last, a face-to-face meeting was convened to seek consensus on which outcomes were critical to include and to ratify the final COS. RESULTS: From 37 eligible papers in the review, we identified and included 48 candidate outcomes in the survey. We sent invitations to 165 people registered to take part in the survey; of these, 102 (62%) completed Round 1, and 80 (78%) completed Round 2 (three young people, 16 parents, 61 professionals). In Round 2 we included four additional outcomes suggested by participants in Round 1. The consensus meeting included two young people, four parents, and nine professionals who were eligible to vote and ratified the COS as 39 outcomes across 10 domains. SIGNIFICANCE: Our methodology was a proportionate and pragmatic approach toward producing a COS for evaluating research on interventions aiming to improve the health of children with RE.

Benign childhood epilepsy with centrotemporal spikes (BECTS) and developmental co-ordination disorder.

BACKGROUND: Benign epilepsy with centro-temporal spikes (BECTS) is a common childhood epilepsy syndrome also known as Rolandic Epilepsy (RE). Neurocognitive phenotypes have been described with greater focus on attention, reading and language domains but there have been far fewer studies focusing on motor functioning. This study included measures of motor, language and cognition in order to investigate the range, degree and pattern of difficulties associated with BECTS in a case series of children, but with a particular emphasis on motor skills. METHOD: Twenty-one children aged between 8 and 16years with a diagnosis of BECTS were asked to complete standardized assessments for language, cognition, motor functioning and handwriting. RESULTS: When measuring across language, cognitive and motor domains, 19 (90.48%) of the twenty-one children with a diagnosis of BECTS showed some difficulties on at least one area of functioning using standardized assessment tests. Of particular note nearly half (47.62%) of the children had some difficulties in one or more areas of motor functioning. DISCUSSION: Children with BECTS have a heterogeneous pattern of neurocognitive impairments. The presence of motor difficulties (DCD) should be considered in all children routinely seen in clinical settings with BECTS and included in any screening processes.

Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy.

BACKGROUND: Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy. METHODS: We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based comparative genome hybridisation. RESULTS: 8.8 % (7/80) of the patients had at least one rare CNVs that was considered to be pathogenic or likely pathogenic. The CNVs involved known disease genes (EHMT1, MBD5 and SCN1A) and imbalances in genomic regions associated with neurodevelopmental disorders (16p11.2, 16p13.11 and 2q13). Prompted by the observation of two deletions disrupting SCN1A we undertook further testing of this gene in selected patients. This led to the identification of four pathogenic SCN1A mutations in our cohort. CONCLUSIONS: We identified five rare de novo deletions and confirmed the clinical utility of array analysis in patients with ID/DD and childhood-onset epilepsy. This report adds to our clinical understanding of these rare genomic disorders and highlights SCN1A mutations as a cause of ID and epilepsy, which can easily be overlooked in adults.

Resting-state oscillatory dynamics in sensorimotor cortex in benign epilepsy with centro-temporal spikes and typical brain development.

Benign Epilepsy with Centro-Temporal Spikes (BECTS) is a common childhood epilepsy associated with deficits in several neurocognitive domains. Neurophysiological studies in BECTS often focus on centro-temporal spikes, but these correlate poorly with morphology and cognitive impairments. To better understand the neural profile of BECTS, we studied background brain oscillations, thought to be integrally involved in neural network communication, in sensorimotor areas. We used independent component analysis of temporally correlated sources on magnetoencephalography recordings to assess sensorimotor resting-state network activity in BECTS patients and typically developing controls. We also investigated the variability of oscillatory characteristics within focal primary motor cortex (M1), localized with a separate finger abduction task. We hypothesized that background oscillations would differ between patients and controls in the sensorimotor network but not elsewhere, especially in the beta band (13-30 Hz) because of its role in network communication and motor processing. The results support our hypothesis: in the sensorimotor network, patients had a greater variability in oscillatory amplitude compared to controls, whereas there was no difference in the visual network. Network measures did not correlate with age. The coefficient of variation of resting M1 peak frequency correlated negatively with age in the beta band only, and was greater than average for a number of patients. Our results point toward a "disorganized" functional sensorimotor network in BECTS, supporting a neurodevelopmental delay in sensorimotor cortex. Our findings further suggest that investigating the variability of oscillatory peak frequency may be a useful tool to investigate deficits of disorganization in neurodevelopmental disorders.

Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum.

AIM: Benign hereditary chorea is a dominantly inherited, childhood-onset hyperkinetic movement disorder characterized by non-progressive chorea and variable degrees of thyroid and respiratory involvement. Loss-of-function mutations in NKX2.1, a gene vital to the normal development and function of the brain, lungs, and thyroid, have been identified in a number of individuals. METHOD: Clinical data from individuals with benign hereditary chorea identified through paediatric neurology services were collected in a standardized format. The NKX2.1 gene was analysed by Sanger sequencing, multiplex ligation-dependent probe amplification, and microarray analysis. RESULTS: Six of our cohort were female and four male, median age at assessment was 8 years 6 months (range 1 y 6 mo-18 y). We identified 10 probands with NKX2.1 mutations; nine of these mutations are novel (including two whole-gene deletions) and one has been previously reported. Of the 10 individuals, eight presented with muscle hypotonia and four had evidence of hypothyroidism or respiratory involvement. Only three out of the 10 individuals had the full triad of 'brain-lung-thyroid syndrome' symptoms. Additional clinical characteristics occurring in individual participants included growth hormone deficiency, pes cavus, kyphosis, duplex kidney, and obsessive-compulsive disorder. INTERPRETATION: Our data suggest that the neurological phenotype is prominent in this condition and that many patients with benign hereditary chorea do not have the classic triad of brain-lung-thyroid syndrome. The extended phenotype may include obsessive-compulsive disorder and skeletal abnormalities.

Neuropsychiatric disease in patients with periventricular heterotopia.

Periventricular heterotopia (PH) is a disorder of neuronal migration. Previous clinical reports of PH have largely focused on the seizure-related and neurodevelopmental consequences of this condition. The authors report four unrelated individuals with PH, with particular emphasis on their behavioral and psychiatric morbidity. A review of the literature suggests that neuropsychiatric presentations are an underrecognized consequence of PH. Clinicians need to be alert to psychiatric complications associated with PH and related disorders of neuronal migration.

Neurosurgical input at pre-natal counselling for parents of babies with Spina bifida.

Prenatal counselling can be helpful to parents in making a decision with regard to continuation of the pregnancy or to help prepare for the birth and the future life of a child with Spina bifida. We aimed to assess the effectiveness of our specialist neuro counselling sessions and to highlight areas that could be improved upon. This was in the form of a questionnaire given to parents, who had been through the counselling and continued with their pregnancy. The areas highlighted for improvement were more explicit information about urinary catheterisation, the need for admission to the special care baby unit (SCBU) and the need for an information leaflet on Spina bifida.

Neural tube defects in Wales: changing demographics from 1998 to 2009.

OBJECTIVE: To establish if there is evidence for the perceived increase in the number of live births with a Neural tube defect (NTD) in South Wales from 1998 to 2009. METHODS: Data was obtained from the Congenital Abnormalities Register Information Services (CARIS), which recorded 305 cases of pregnancies involving neural tube defects. Descriptive analysis was carried out for each year in this period to obtain the number of live births, the proportion of live births compared to NTD pregnancies, plus the number and the percentage terminated each year. RESULTS: From the 305 cases, 66 resulted in live births, 230 in terminations. There was an increase in live births from 13.8% in 1998 to 33.3% in 2009, and a decrease in terminations from 82.76% in 1998 to 62.50% in 2009. The data also showed that this increase occurred mainly in the South of Wales. Discussion. Over this time period, there has been a decrease in the number of pregnancies affected by a neural tube defect and a decline in the proportion of pregnancies with neural tube defects resulting in terminations. Consequently, there has been an increase in the number of live births. The reasons for this change in trend is unclear, it may be that prospective parents are more willing to proceed with the pregnancy due to better support and services and the improved prognosis for children with neural tube defects. CONCLUSION: This data clearly shows that the number of children born with a NTD is increasing, and if this trend persists, services will have to expand and adapt to the change in the demographic of this population.

A recent surge of fulminant and early onset subacute sclerosing panencephalitis (SSPE) in the United Kingdom: An emergence in a time of measles.

BACKGROUND: Subacute Sclerosing Panencephalitis (SSPE) is a fatal progressive neurological disorder following measles infection. METHODS: Cases were collated from Paediatric Neurology centres in the UK over 24 months from 2017 to 2019 and represent all cases referred to the National Viral Reference Department (VRD). Diagnosis was established with detection of a raised measles index, demonstrating intrathecal measles antibody production. FINDINGS: Six children presented with SSPE over two years, with median age five years (range 2-7 years) and median latency period three years (range 2-6 years). The majority were exposed to measles during infancy. Atypical features were common, including visual impairment, focal and generalised tonic-clonic seizures, headache, vomiting and movement disorders. EEG demonstrated typical features in five cases, though not always at presentation. Initial MRI was normal in four cases, with two showing focal and widespread white matter changes. Antiviral and immunomodulatory treatment led to minimal or no improvement. All progressed to cognitive regression, seizures and neurological decline within six months. INTERPRETATION: These cases demonstrate the highest incidence of SSPE in the UK since 2000, all progressing to acute fulminant disease, following younger age of onset, short latency period and atypical presentations. Recent global surges in measles cases raise the importance of clinician awareness of SSPE as a potential diagnosis in children with neurological regression. Herd immunity remains the key protective mechanism for infants and groups that cannot be vaccinated. Health care providers, educators and governments must ensure resources continue to target effective education and access to immunisation programmes, the only means to combat this devastating and fatal condition.

Sleep and epilepsy: unfortunate bedfellows.

The relationship between sleep and seizure disorders is a particularly vicious cycle. Nocturnal seizures can interrupt sleep while a number of factors, including antiepileptics and sleep disorders that cause sleep fragmentation, can worsen seizures. Understanding and managing seizures and related sleep disturbance is therefore an important and treatable intervention target that could potentially improve children's sleep, but also their learning, mood, behaviour, seizures and parental quality of life.

Diagnosis of sporadic neurofibromatosis type 2 in the paediatric population.

OBJECTIVE: Onset of symptoms in severe sporadic neurofibromatosis type 2 (NF2) is typically within childhood; however, there is poor awareness of presenting features in young children, potentially resulting in delayed diagnosis and poorer outcome. We have reviewed presentation of sporadic paediatric NF2 to raise awareness of early features, highlighting those requiring further investigation. DESIGN: Patients diagnosed with NF2 at age ≤16 and seen between 2012 and 2015 were notified via the British Paediatric Neurology Surveillance Unit or identified through the English NF2 service. RESULTS: Epidemiological data estimate that 1 in 110 611 births are affected with childhood-onset NF2. Notes of 32 patients with sporadic NF2 were reviewed. Of those presenting under the age of 5, 89% (17/19) had ocular, 74% (14/19) dermatological and 58% (11/19) neurological signs; in 84% (16/19) features were multisystemic. Sixty-six per cent (21/32) had ≥1 atypical feature, including cerebellar hypoplasia in three cases (9%) and focal cortical dysplasia in five out of seven seizure-related presentations. Five cases presented with a sometimes transient or intermittent cranial nerve mononeuropathy. The mean delay to diagnosis was 3.16 years; in eight cases (25%) this exceeded 6 years. Most significant delay occurred in mononeuropathy, ophthalmological and/or seizure presentations, with a mean delay of 3, 4.5 and 6 years, respectively. Eighty-four per cent (27/32) of cases needed intervention in childhood. CONCLUSIONS: All non-vestibular schwannoma NF2 presentations in childhood had significant diagnostic delay. We emphasise the importance of detailed assessment of skin and eyes in unusual presentations and propose an aide to prompt timely referral to specialist services.

Clinical features, course, and outcomes of a UK cohort of pediatric moyamoya.

OBJECTIVE: To describe characteristics and course of a large UK cohort of children with moyamoya from multiple centers and examine prognostic predictors. METHODS: Retrospective review of case notes/radiology, with use of logistic regression to explore predictors of outcome. RESULTS: Eighty-eight children (median presentation age 5.1 years) were included. Thirty-six presented with arterial ischemic stroke (AIS) and 29 with TIA. Eighty had bilateral and 8 unilateral carotid circulation disease; 29 patients had posterior circulation involvement. Acute infarction was present in 36/176 hemispheres and chronic infarction in 86/176 hemispheres at the index presentation. Sixty-two of 82 with symptomatic presentation had at least one clinical recurrence. Fifty-five patients were treated surgically, with 37 experiencing fewer recurrences after surgery. Outcome was categorized as good using the Recovery and Recurrence Questionnaire in 39/85 patients. On multivariable analysis, presentation with TIA (odds ratio [OR] 0.09, 95% confidence interval [CI] 0.02-0.35), headache (OR 0.10, 95% CI 0.02-0.58), or no symptoms (OR 0.08, 95% CI 0.01-0.68) was less likely to predict poor outcome than AIS presentation. Posterior circulation involvement predicted poor outcome (OR 4.22, 95% CI 1.23-15.53). Surgical revascularization was not a significant predictor of outcome. CONCLUSIONS: Moyamoya is associated with multiple recurrences, progressive arteriopathy, and poor outcome in half of patients, especially with AIS presentation and posterior circulation involvement. Recurrent AIS is rare after surgery. Surgery was not a determinant of overall outcome, likely reflecting surgical case selection and presentation clinical status.

Core Health Outcomes In Childhood Epilepsy (CHOICE): protocol for the selection of a core outcome set.

BACKGROUND: There is increasing recognition that establishing a core set of outcomes to be evaluated and reported in trials of interventions for particular conditions will improve the usefulness of health research. There is no established core outcome set for childhood epilepsy. The aim of this work is to select a core outcome set to be used in evaluative research of interventions for children with rolandic epilepsy, as an exemplar of common childhood epilepsy syndromes. METHODS: First we will identify what outcomes should be measured; then we will decide how to measure those outcomes. We will engage relevant UK charities and health professional societies as partners, and convene advisory panels for young people with epilepsy and parents of children with epilepsy. We will identify candidate outcomes from a search for trials of interventions for childhood epilepsy, statutory guidance and consultation with our advisory panels. Families, charities and health, education and neuropsychology professionals will be invited to participate in a Delphi survey following recommended practices in the development of core outcome sets. Participants will be able to recommend additional outcome domains. Over three rounds of Delphi survey participants will rate the importance of candidate outcome domains and state the rationale for their decisions. Over the three rounds we will seek consensus across and between families and health professionals on the more important outcomes. A face-to-face meeting will be convened to ratify the core outcome set. We will then review and recommend ways to measure the shortlisted outcomes using clinical assessment and/or patient-reported outcome measures. DISCUSSION: Our methodology is a proportionate and pragmatic approach to expediently produce a core outcome set for evaluative research of interventions aiming to improve the health of children with epilepsy. A number of decisions have to be made when designing a study to develop a core outcome set including defining the scope, choosing which stakeholders to engage, most effective ways to elicit their views, especially children and a potential role for qualitative research.

Unusual neurological presentation of Fusobacterium necrophorum disease.

A 2-year-old girl presented to hospital, with reduced consciousness and fever. She had a 4-week history of fever treated with two courses of amoxicillin for tonsillitis diagnosed in primary care. Neuroimaging revealed multiple cerebral abscesses and subdural empyema. Pus aspirated from the intracranial collections grew Fusobacterium necrophorum and meropenem was started. Following neurosurgery, the patient continued to be agitated with fluctuating fever. She underwent close monitoring with regular neuroimaging. To control the progression of intracranial infection, she underwent three separate neurosurgical procedures following which she made a good recovery. This case demonstrates how an organism rarely associated with childhood illnesses presented atypically and progressed into a complex potentially fatal intracranial infection requiring a high degree of neurosurgical intervention. Awareness of this organism is important. The combination of source control together with appropriate antibiotic use was crucial in controlling the infection.

Ipsilateral cortical motor desynchronisation is reduced in Benign Epilepsy with Centro-Temporal Spikes.

OBJECTIVE: Magnetoencephalography (MEG) and a simple motor paradigm were used to study induced sensorimotor responses and their relationship to motor skills in children diagnosed with Benign Epilepsy with Centro-Temporal Spikes (BECTS). METHODS: Twenty-one children with BECTS and 15 age-matched controls completed a finger abduction task in MEG; movement-related oscillatory responses were derived and contrasted between groups. A subset of children also completed psycho-behavioural assessments. Regression analyses explored the relationship of MEG responses to manual dexterity performance, and dependence upon clinical characteristics. RESULTS: In children with BECTS, manual dexterity was below the population mean (p=.002) and three showed severe impairment. Our main significant finding was of reduced ipsilateral movement related beta desynchrony (MRBDi) in BECTS relative to the control group (p=.03) and predicted by epileptic seizure recency (p=.02), but not age, medication status, or duration of epilepsy. Laterality scores across the entire cohort indicated that less lateralised MRBD predicted better manual dexterity (p=.04). CONCLUSIONS: Altered movement-related oscillatory responses in ipsilateral motor cortex were associated with motor skill deficits in children with BECTS. These changes were more marked in those with more recent seizures. SIGNIFICANCE: These findings may reflect differences in inter-hemispheric interactions during motor control in BECTS.