Liam Dorris

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial

__Background__ In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. __Methods__ In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks’ postmenstrual age who were born at more than 26 weeks’ gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-totreat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. __Findings__ Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41–70). The mean FSIQ score was 99·08 (SD 18·35) in the awake-regional anaesthesia group and 98·97 (19·66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0·23 (95% CI –2·59 to 3·06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. __Interpretation__ Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population.Summary Background There is pre-clinical evidence that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia may have an increased risk of poorer neurodevelopmental outcome. This trial aims to determine if GA in infancy has any impact on neurodevelopmental outcome. The primary outcome for the trial is neurodevelopmental outcome at 5 years of age. The secondary outcome is neurodevelopmental outcome at two years of age and is reported here. Methods We performed an international assessor-masked randomised controlled equivalence trial in infants less than 60 weeks post-menstrual age, born at greater than 26 weeks gestational age having inguinal herniorrhaphy. Infants were excluded if they had existing risk factors for neurologic injury. Infants were randomly assigned to awake-regional (RA) or sevoflurane-based general anaesthesia (GA). Web-based randomisation was performed in blocks of two or four and stratified by site and gestational age at birth. The outcome for analysis was the composite cognitive score of the Bayley Scales of Infant and Toddler Development, Third Edition. The analysis was as-per-protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. The trial was registered at ANZCTR, ACTRN12606000441516 and ClinicalTrials.gov, NCT00756600. Findings Between February 2007, and January 2013, 363 infants were randomised to RA and 359 to GA. Outcome data were available for 238 in the RA and 294 in the GA arms. The median duration of anaesthesia in the GA arm was 54 minutes. For the cognitive composite score there was equivalence in means between arms (RA-GA: +0·169, 95% CI −2·30 to +2·64). Interpretation For this secondary outcome we found no evidence that just under an hour of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at two years of age compared to RA.

Quality of life in children with acquired brain injury: Parent perspectives 1–5 years after injury

Primary objective: To obtain parental ratings of childrens quality of life, cognitive, emotional and behavioural functioning, as well as ratings of service provision, following traumatic brain injury (TBI). Research design: A retrospective, cross-sectional study. Methods and procedures: Parents of 47 children with mild or moderate–severe TBI completed standardized questionnaires evaluating quality of life (PedsQL 4.0) and cognitive, emotional and behavioural functioning (Strengths and Difficulties Questionnaire). Data collected was compared with published normative data for these scales. Views regarding parental experiences of care and their ratings of service provision were also obtained. Results: Quality of life was significantly lower in 13-times as many children with TBI than expected from the normative population. Parents reported that more than 43% of children with TBI had cognitive, emotional and behavioural difficulties that impacted on their daily life. Whilst high levels of social deprivation were found, this did not fully explain the significantly raised levels of difficulties. Another factor associated with this poor outcome was the absence of systematic, routine follow-up or intervention. Conclusions: Parents frequently reported poor quality of life and cognitive, emotional and behavioural problems in their children following TBI. These preliminary findings indicate that children, after TBI, are at risk of developing persistent clinical problems and require follow-up beyond the acute period of their recovery.

Development and validation of a measure of the impact of epilepsy on a young person’s quality of life: Glasgow epilepsy outcome scale for young persons (GEOS-YP)

OBJECTIVE The goal of the work described here was to develop and validate a measure of the impact of epilepsy on an adolescents quality of life that is based on direct exploration of the adolescents views. METHODS Initial scale development was based on data generated through qualitative methods (focus groups) in a previous study [McEwan MJ, Espie CA, Metcalfe J, Brodie MJ, Wilson MT. Seizure 2004;13:15-31]. A draft measure was piloted (n=30) and refined using correlational methods. Psychometric properties were established by means of a preliminary field trial (n=78). RESULTS An initial item pool of 76 was refined to 50. The structure of the measure mirrored the conceptual model derived from focus group study; Part 1 covered issues relating to adolescent development (identity formation) with five subscales, and Part 2 covered epilepsy-related issues with four subscales. The final GEOS-YP had good internal consistency (alpha=0.91) and test-retest reliability (rho=0.75). Concurrent and construct validity was acceptable, and the GEOS-YP discriminated on dimensions of clinical importance. Participant feedback suggested the measure has excellent face validity and potential clinical utility. CONCLUSIONS The GEOS-YP is a direct measure of how adolescents perceive epilepsy impacts their quality of life. The GEOS-YP has sound psychometric properties and provides a relatively brief and potentially useful clinical outcome tool.

A systematic review of psychological interventions to alleviate cognitive and psychosocial problems in children with acquired brain injury

Aim  It is now generally accepted that paediatric acquired brain injury (ABI) can have an impact on a child’s cognitive, social, and behavioural functioning. However, the lack of guidelines on effective interventions for the affected children and their families, particularly beyond the acute recovery phase, can limit access to effective support. We provide a systematic review of the literature on the effectiveness of psychological interventions aimed at alleviating cognitive and psychosocial outcomes after paediatric ABI.

Apnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes, a Randomized Controlled Trial

Background:Postoperative apnea is a complication in young infants. Awake regional anesthesia (RA) may reduce the risk; however, the evidence is weak. The General Anesthesia compared to Spinal anesthesia study is a randomized, controlled trial designed to assess the influence of general anesthesia (GA) on neurodevelopment. A secondary aim is to compare rates of apnea after anesthesia. Methods:Infants aged 60 weeks or younger, postmenstrual age scheduled for inguinal herniorrhaphy, were randomized to RA or GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born less than 26 weeks gestation. The primary outcome of this analysis was any observed apnea up to 12 h postoperatively. Apnea assessment was unblinded. Results:Three hundred sixty-three patients were assigned to RA and 359 to GA. Overall, the incidence of apnea (0 to 12 h) was similar between arms (3% in RA and 4% in GA arms; odds ratio [OR], 0.63; 95% CI, 0.31 to 1.30, P = 0.2133); however, the incidence of early apnea (0 to 30 min) was lower in the RA arm (1 vs. 3%; OR, 0.20; 95% CI, 0.05 to 0.91; P = 0.0367). The incidence of late apnea (30 min to 12 h) was 2% in both RA and GA arms (OR, 1.17; 95% CI, 0.41 to 3.33; P = 0.7688). The strongest predictor of apnea was prematurity (OR, 21.87; 95% CI, 4.38 to 109.24), and 96% of infants with apnea were premature. Conclusions:RA in infants undergoing inguinal herniorrhaphy reduces apnea in the early postoperative period. Cardiorespiratory monitoring should be used for all ex-premature infants.

Sleep problems in children with neurological disorders

This review describes the complex and often reciprocal relationship between sleep problems, neurological disorders and/or intellectual disability in children. The causes of Intellectual disability (ID) discussed in this review include those conditions present from or around the time of birth, although it also considers traumatic brain injuries occurring later in development. This review discusses the patterns of sleep difficulty associated with specific disorders and summarizes the assessment and interventions, both behavioural and pharmacological, applicable to children. Many neurological disorders such as epilepsy, narcolepsy and neurorespiratory disorders vary considerably in terms of the degree of co-morbid problems and can present with a spectrum of effects on underlying cognitive or behavioural substrates including sleep function. These conditions are discussed as they provide useful insights into how disordered sleep can impact on cognitive development and behaviour. The review draws both on the literature in these areas and the extensive clinical experience of the authors.

Memory consolidation and accelerated forgetting in children with idiopathic generalized epilepsy

Whether children with idiopathic generalized epilepsy exhibit accelerated forgetting of verbal and nonverbal information in comparison to healthy controls matched for age and IQ was explored. Twenty-one children with IGE were compared with 21 healthy controls on measures of verbal and visuospatial memory at delays of 30 minutes and 1 week by use of a minimum-learning criterion controlled for initial learning. For the auditory-verbal memory test, group performance was comparable at 30 minutes, but children with IGE recalled significantly less than controls at 1 week. When the number of learning trials to criterion was controlled, the main effects of group and delay became nonsignificant. No group differences were found with respect to recognition performance. Comparisons for the visuospatial task were nonsignificant. Overall, poor initial learning efficiency led to retrieval difficulties, specifically at the longer delay, and was more common in the IGE group. These results, although preliminary, have implications for education planning in childhood IGE.

The clinical utility of an SCN1A genetic diagnosis in infantile‐onset epilepsy

Aim  Genetic testing in the epilepsies is becoming an increasingly accessible clinical tool. Mutations in the sodium channel alpha 1 subunit (SCN1A) gene are most notably associated with Dravet syndrome. This is the first study to assess the impact of SCN1A testing on patient management from both carer and physician perspectives.

Comorbidities and predictors of health‐related quality of life in Dravet syndrome

Purpose:  Health‐related quality of life (HRQOL) has emerged as a widely accepted measure to evaluate how chronic disease impacts on an individual’s physical, social, and mental well‐being. There is a paucity of data focusing on HRQOL in specific epilepsy syndromes and their associated needs. In this study our aim was to describe the comorbidities and disease‐related predictors for HRQOL in Dravet syndrome, an epileptic encephalopathy, with defined genetic etiology. We anticipate that this will help us to better recognize and understand the needs of children and families and aid treatment planning in this severe epilepsy syndrome.

Psychosocial and intellectual functioning in childhood narcolepsy

Purpose: This study reports the psychological assessment of 12 children referred to a narcolepsy clinic, using quantitative methods to describe intellectual and psychosocial functioning in childhood narcolepsy. Methods: The participants were six males and six females aged between 7–16 years (median age 10 years). The protocol included a clinical interview; the Wechsler Intelligence Scale for Children-III-UK; and the Parent version of the Achenbach Child Behaviour Checklist (CBCL). Results: Eleven children obtained an IQ in the average range (mean and median = 100). However, a significant difference was found between verbal and performance scales in 42% of children, compared to WISC-III normative prevalence rates of 24%. CBCL results revealed that 10/12 children scored in the clinically significant range on the Total Score Index, with 9/12 obtaining scores in the significant range on the Internalizing Index. The majority of children presented with difficulties in discussing and describing distressing physical and psychological symptoms with parents and others. Conclusions: These findings suggest that the psychosocial impact of narcolepsy extends beyond the effects of excessive sleepiness and that symptoms such as hallucinations can lead to significant psychological morbidity.