Comparative Efficacy and Side Effect Profiles of Interventions for Pediatric Saliva Control: A Cohort Study.

OBJECTIVE: To compare efficacy and side effect profile data on conservative, behavioral, pharmacological, and surgical treatments used for pediatric saliva control. STUDY DESIGN: A cohort study of children (n = 483) referred to a specialty Saliva Control service between May 2014 and November 2019 was performed, using quantitative data from pretreatment and post-treatment questionnaires (the Drooling Impact Scale [DIS], Drooling Rating Scale [DRS]) and recording of side effects. Overall, 483 children were included; treatment choices were based on published international guidelines. RESULTS: The greatest improvement was seen after intraglandular botulinum toxin A (BTX-A) injections (n = 207; 551 courses; mean DIS change, 34.7; 95% CI = 29.2-35.7) or duct transpositional surgery (n = 31; mean change in DIS, 29.0; 95% CI, 22.3-35.7). Oral anticholinergics were associated with good outcomes, with no significant statistical difference between glycopyrronium bromide (n = 150; mean DIS change, 21.5; 95% CI, 19.1-24.0) or trihexyphenidyl (n = 87; mean DIS change, 22.4; 95% CI, 18.9-25.8). Inhaled ipratropium bromide was not as efficacious (n = 80; mean DIS change, 11.1; 95% CI, 8.9-13.3). Oromotor programs were used in a selected group with reliable outcomes (n = 9; mean DIS change, 13.0). Side effects were consistent with previous studies. Overall, in cases of milder severity, enterally administered therapies provided a good first-line option. With more severe problems, BTX-A injections or saliva duct transpositional surgery were more effective and well tolerated. CONCLUSIONS: We describe a large, single-center pediatric saliva control cohort, providing direct comparison of the efficacy and side effect profiles for all available interventions and inform clinical practice for specialists when considering different options. BTX-A injections or saliva duct transpositional surgery seem to be more effective for saliva control that is more severe.

Impact of and research priorities in early onset epilepsy: An investigation of parental concerns.

[Background and aim] Early onset epilepsy is a neurological condition with significant developmental consequences, and presents affected children and families with challenges which pervade many aspects of family life. Whilst the concerns of parents and the impact on quality of life is well documented in qualitative research, little emphasis has been placed on the context of 'early onset', and the implications of these concerns for research priority setting. We aimed to explore parental perspectives regarding concerns and the impact of early onset epilepsy on the child and family, and to identify priorities for future paediatric epilepsy research. [Methods] The Brain development in Early Epilepsy: Parent Priorities (BEE-PP) project employed a mixed methods approach to collect information on parents' experience of having a child diagnosed with early onset epilepsy before 36 months old and aged up to 16 years old. Parents completed an online survey (n = 15) followed by a focus group (n = 5) to explore their main concerns regarding early onset epilepsy, the impact on family life and research priorities. [Results] A thematic analysis of the focus group data generated eight themes related to concerns of parents, the impact on the family and research priorities. The three main concerns identified were the expected trajectory of their child's development, a lack of seizure control following diagnosis and adverse behavioural side effects of medication. Within family life, early onset epilepsy had an impact on sibling autonomy and psychosocial adaptation, poorer parental wellbeing and restricted social and personal activities. The need for clearer information regarding their child's developmental trajectory, and managing the side effects of medication and their interactions with behaviour over time were topics of priority for future epilepsy research. [Interpretation] The impact of early onset epilepsy on the family is pervasive and requires the provision of appropriate healthcare service-led support for families to improve quality of life and children's adjustment to epilepsy. Regular monitoring of the concerns of parents and the impact of the diagnosis would be beneficial for addressing epilepsy-related and psychosocial needs of the wider family throughout their child's development. Implications for future research priority setting with regards to improved clinician-to-parent information sharing and managing the behavioural side effects of medication are discussed.

Neurological and cognitive outcomes after antibody-negative autoimmune encephalitis in children.

AIM: To characterize the neurological and cognitive outcomes in children with antibody-negative autoimmune encephalitis (Ab-negative AE). METHOD: A cohort of children presenting to our institution over a 10-year period with autoimmune encephalitis was identified by structured retrospective review of medical records. Clinical features at presentation and final follow-up were recorded. Neuropsychological testing was performed in a subset of patients. Outcomes after Ab-negative AE were compared with outcomes after N-methyl-D-aspartate receptor antibody encephalitis (NMDARE). RESULTS: Forty-four patients (26 females, 18 males, median age 9y 2mo [interquartile range 4y 5mo-11y 8mo], 23 with NMDARE) with a diagnosis of autoimmune encephalitis were included. Postencephalitic epilepsy was more frequent after Ab-negative AE compared to NMDARE (61% vs 14%, p=0.002). Cognitive testing was performed in a subset of patients (n=21; Ab-negative AE=11, NMDARE=10). Full-scale IQ was lower after Ab-negative AE than NMDARE (mean IQ 75 vs 92, p=0.02), primarily because of reduced verbal comprehension index (80 vs 98, p=0.01) and working memory index (77 vs 95, p=0.09). The cognitive function most commonly impaired was executive function (80% [8/10] vs 22% [2/9]). INTERPRETATION: Ab-negative AE was associated with poorer cognitive outcomes than NMDARE at 1-year follow-up. Further studies are required to evaluate if immunotherapy can be optimized to improve outcome.

Avoidant/restrictive food intake disorder and autism spectrum disorder: clinical implications for assessment and management.

AIM: We examined clinical and neurodevelopmental presentations of children with avoidant/restrictive food intake disorder (ARFID) to inform clinical assessment and management. METHOD: Five hundred and thirty-six patients (mean age 6y 10mo, SD 3y 5mo, range 10mo-20y; 401 males, 135 females) seen by the tertiary multidisciplinary feeding service at the Evelina London Children's Hospital between January 2013 and June 2019 were included in this case-control study. These children experienced significant feeding difficulties impacting nutrition, development, and psychosocial functioning requiring tertiary specialized input. Data on ARFID diagnosis, demographics, comorbidity, and nutrition was extracted from electronic patient records. RESULTS: Forty-nine per cent of children met ARFID criteria. The remaining participants had other difficulties including feeding, medical, and/or neurodevelopmental conditions. ARFID is more prevalent among younger patients (4-9 years) and in children with comorbid autism spectrum disorder (ASD). Younger age, comorbid ASD, and male sex significantly predicted ARFID. Diet range and male sex significantly predicted nutritional inadequacy, while comorbid ASD did not. A trend was seen between younger age and nutritional inadequacy. INTERPRETATION: Young children with ARFID should raise suspicion for ASD. Although significant nutritional deficiencies are common in children with comorbid ARFID and ASD, they are correctable with nutritional supplementation. Specialty perspective potentially limits generalizability of findings to community feeding services. We also emphasize the importance of early identification of nutritional deficits and management.

Incidence of paediatric multiple sclerosis and other acquired demyelinating syndromes: 10-year follow-up surveillance study.

AIM: To describe a 10-year follow-up of children (<16y) with acquired demyelinating syndromes (ADS) from a UK-wide prospective surveillance study. METHOD: Diagnoses were retrieved from the patients' records via the patients' paediatric or adult neurologist using a questionnaire. Demyelinating phenotypes at follow-up were classified by an expert review panel. RESULTS: Twenty-four out of 125 (19.2%) children (64 males, 61 females; median age 10y, range 1y 4mo-15y 11mo), identified in the original study, were diagnosed with multiple sclerosis (incidence of 2.04/million children/year); 23 of 24 fulfilled 2017 McDonald criteria at onset. Aquaporin-4-antibody neuromyelitis optica spectrum disorders were diagnosed in three (2.4%, 0.26/million children/year), and relapsing myelin oligodendrocyte glycoprotein antibody-associated disease in five (4%, 0.43/million children/year). Three out of 125 seronegative patients relapsed and 85 of 125 (68%) remained monophasic over 10 years. Five of 125 patients (4%) originally diagnosed with ADS were reclassified during follow-up: three children diagnosed initially with acute disseminated encephalomyelitis were subsequently diagnosed with acute necrotising encephalopathy (RAN-binding protein 2 mutation), primary haemophagocytic lymphohistiocytosis (Munc 13-4 gene inversion), and anti-N-methyl-d-aspartate receptor encephalitis. One child initially diagnosed with optic neuritis was later diagnosed with vitamin B12 deficiency, and one presenting with transverse myelitis was subsequently diagnosed with Sjögren syndrome. INTERPRETATION: The majority of ADS presentations in children are monophasic, even at 10-year follow-up. Given the implications for treatment strategies, multiple sclerosis and central nervous system autoantibody mimics warrant extensive investigation.

ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder.

ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children. New individuals were identified through GeneMatcher, ClinVar and the European Network for Therapies in Rare Epilepsy (NETRE). Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria. Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n = 8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n = 4); (iii) unclassified (n = 8). Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable. Dysmorphic features were variable. Variants were distributed across the gene and mostly de novo with no precise genotype-phenotype correlation. ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE. More detailed epilepsy descriptions of larger cohorts and functional studies might reveal genotype-phenotype correlation. The epileptogenic mechanism may be linked to interaction with histone H3.3.

Is cognitive inflexibility a missing link? The role of cognitive inflexibility, alexithymia and intolerance of uncertainty in externalising and internalising behaviours in young people with autism spectrum disorder.

BACKGROUND: Internalising (anxiety and low mood) and externalising (aggressive or outburst behaviours, and irritability) difficulties are very common in autism spectrum disorder (ASD) across the life span, relatively stable over time and often associated with poorer quality of life. Understanding the cognitive mechanisms underlying internalising and externalising difficulties in ASD is essential for developing targeted supports and interventions. In the present study, we investigated established and less-researched cognitive factors hypothesised to contribute to internalising and/or externalising difficulties in ASD, namely cognitive inflexibility (CI), intolerance of uncertainty (IU) and alexithymia. Based on previous models and clinical experience, we hypothesised that IU would lead to internalising symptoms, with alexithymia contributing to this pathway, and that CI would have a direct effect on externalising behaviours and may indirectly contribute to internalising symptoms via increasing IU. METHODS: Our sample consisted of 95 5- to 18-year-olds presenting to a specialist neurodevelopmental clinic and receiving a diagnosis of ASD. Parents/caregivers completed questionnaires assessing ASD symptomatology, internalising and externalising difficulties, CI, IU and alexithymia. Structural equation modelling was used to examine the hypothesised pathways and relationships between the main variables of interest. RESULTS: Cognitive Inflexibility played a significant direct role in the pathway from ASD symptoms to externalising symptoms in ASD, and indirect role via IU in the pathway to internalising problems. Relationships between alexithymia and both internalising and externalising symptoms were weaker, with alexithymia predicting internalising difficulties via IU only. CONCLUSIONS: The finding of a direct pathway from CI to externalising behaviours is novel, as is the indirect role of CI in internalising symptomatology. Of the three cognitive mechanisms examined, only CI significantly predicted externalising symptoms. Possible implications for interventions and supports targeting these cognitive processes in ASD are discussed.

Autism spectrum disorder and kidney disease.

Neurodevelopmental impairments have been recognised as a major association of paediatric kidney disease and bladder dysfunction, presenting challenges to clinicians and families to provide reasonable adjustments in order to allow access to investigations and treatments. Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterised by impairments in social interaction/communication and repetitive sensory-motor behaviours. Mental health, learning and physical co-morbidities are common. There is emerging evidence that ASD and kidney disease have some overlaps with genetic copy number variants and environmental factors contributing to shared pathogenesis. Prevalence rates of ASD in kidney disease are currently not known. A high index of suspicion of underlying ASD is required when a young person presents with communication difficulties, anxiety or behaviour that challenges, which should then trigger referral for a neurodevelopmental and behavioural assessment. We discuss practical approaches for providing care, which include understanding methods of communication and sensory, behavioural and environmental adaptations.

Guidance for identification and treatment of individuals with attention deficit/hyperactivity disorder and autism spectrum disorder based upon expert consensus.

BACKGROUND: Individuals with co-occurring hyperactivity disorder/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) can have complex presentations that may complicate diagnosis and treatment. There are established guidelines with regard to the identification and treatment of ADHD and ASD as independent conditions. However, ADHD and ASD were not formally recognised diagnostically as co-occurring conditions until the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) was published in 2013. Hence, awareness and understanding of both conditions when they co-occur is less established and there is little guidance in the clinical literature. This has led to uncertainty among healthcare practitioners when working with children, young people and adults who present with co-existing ADHD and ASD. The United Kingdom ADHD Partnership (UKAP) therefore convened a meeting of professional experts that aimed to address this gap and reach expert consensus on the topic that will aid healthcare practitioners and allied professionals when working with this complex and vulnerable population. METHOD: UK experts from multiple disciplines in the fields of ADHD and ASD convened in London in December 2017. The meeting provided the opportunity to address the complexities of ADHD and ASD as a co-occurring presentation from different perspectives and included presentations, discussion and group work. The authors considered the clinical challenges of working with this complex group of individuals, producing a consensus for a unified approach when working with male and female, children, adolescents and adults with co-occurring ADHD and ASD. This was written up, circulated and endorsed by all authors. RESULTS: The authors reached a consensus of practical recommendations for working across the lifespan with males and females with ADHD and ASD. Consensus was reached on topics of (1) identification and assessment using rating scales, clinical diagnostic interviews and objective supporting assessments; outcomes of assessment, including standards of clinical reporting; (2) non-pharmacological interventions and care management, including psychoeducation, carer interventions/carer training, behavioural/environmental and Cognitive Behavioural Therapy (CBT) approaches; and multi-agency liaison, including educational interventions, career advice, occupational skills and training, and (3) pharmacological treatments. CONCLUSIONS: The guidance and practice recommendations (Tables 1, 4, 5, 7, 8 and 10) will support healthcare practitioners and allied professionals to meet the needs of this complex group from a multidisciplinary perspective. Further research is needed to enhance our understanding of the diagnosis, treatment and management of individuals presenting with comorbid ADHD and ASD.

SCN8A heterozygous variants are associated with anoxic-epileptic seizures.

Anoxic-epileptic seizures (AES) are rare outcomes of common childhood reflex anoxic syncope that trigger a true epileptic seizure. The term AES was coined by Stephenson in 1983, to differentiate these events from convulsive syncopes and the more common reflex anoxic syncopes. A genetic susceptibility for AES has been postulated; but, its molecular basis has up to now been elusive. We report here two illustrative cases and show the association of de novo SCN8A variants and AES. One of them had focal or generalized seizures and autonomic symptoms triggered by orthostatism; the second had breath-holding spells triggered by pain or exercise leading to tonic-clonic seizures; both had repeatedly normal EEGs and a family history of reflex syncope. The data of three additional AES patients further suggest, for the first time, a link between SCN8A pathogenic variants and AES. The neurodevelopment of four patients was abnormal. Four of the five SCN8A mutations observed here were previously described in patients with seizure disorders. Seizures responded particularly well to sodium channel blockers. Our observation enriches the spectrum of seizures linked with SCN8A pathogenic variants.