Background Few studies of how exposure of children to anesthesia may affect neurodevelopment employ comprehensive neuropsychological assessments. This study tested the hypothesis that exposure to multiple, but not single, procedures requiring anesthesia before age 3 yr is associated with adverse neurodevelopmental outcomes. Methods Unexposed, singly exposed, and multiply exposed children born in Olmsted County, Minnesota, from 1994 to 2007 were sampled using a propensity-guided approach and underwent neuropsychological testing at ages 8 to 12 or 15 to 20 yr. The primary outcome was the Full-Scale intelligence quotient standard score of the Wechsler Abbreviated Scale of Intelligence. Secondary outcomes included individual domains from a comprehensive neuropsychological assessment and parent reports. Results In total, 997 children completed testing (411, 380, and 206 unexposed, singly exposed, and multiply exposed, respectively). The primary outcome of intelligence quotient did not differ significantly according to exposure status; multiply exposed and singly exposed children scoring 1.3 points (95% CI, −3.8 to 1.2; P = 0.32) and 0.5 points (95% CI, −2.8 to 1.9; P = 0.70) lower than unexposed children, respectively. For secondary outcomes, processing speed and fine motor abilities were decreased in multiply but not singly exposed children; other domains did not differ. The parents of multiply exposed children reported increased problems related to executive function, behavior, and reading. Conclusions Anesthesia exposure before age 3 yr was not associated with deficits in the primary outcome of general intelligence. Although secondary outcomes must be interpreted cautiously, they suggest the hypothesis that multiple, but not single, exposures are associated with a pattern of changes in specific neuropsychological domains that is associated with behavioral and learning difficulties.

Background Exposure of young animals to general anesthesia causes neurodegeneration and lasting behavioral abnormalities; whether these findings translate to children remains unclear. This study used a population-based birth cohort to test the hypothesis that multiple, but not single, exposures to procedures requiring general anesthesia before age 3 yr are associated with adverse neurodevelopmental outcomes. Methods A retrospective study cohort was assembled from children born in Olmsted County, Minnesota, from 1996 to 2000 (inclusive). Propensity matching selected children exposed and not exposed to general anesthesia before age 3 yr. Outcomes ascertained via medical and school records included learning disabilities, attention-deficit/hyperactivity disorder, and group-administered ability and achievement tests. Analysis methods included proportional hazard regression models and mixed linear models. Results For the 116 multiply exposed, 457 singly exposed, and 463 unexposed children analyzed, multiple, but not single, exposures were associated with an increased frequency of both learning disabilities and attention-deficit/hyperactivity disorder (hazard ratio for learning disabilities = 2.17 [95% CI, 1.32 to 3.59], unexposed as reference). Multiple exposures were associated with decreases in both cognitive ability and academic achievement. Single exposures were associated with modest decreases in reading and language achievement but not cognitive ability. Conclusions These findings in children anesthetized with modern techniques largely confirm those found in an older birth cohort and provide additional evidence that children with multiple exposures are more likely to develop adverse outcomes related to learning and attention. Although a robust association was observed, these data do not determine whether anesthesia per se is causal.

In the largest sample studied to date, we measured cognitive functioning in children and adolescents with pediatric multiple sclerosis (n =187) as well as those with clinically isolated syndrome (n =44). Participants were consecutively enrolled from six United States PediatricMultiple Sclerosis Centers of Excellence. Participants had amean of 14.8 ± 2.6 years of age and an average disease duration of 1.9 ± 2.2 years. A total of 65 (35%) children with multiple sclerosis and 8 (18%) with clinically isolated syndrome met criteria for cognitive impairment. The most frequent areas involved were fine motor coordination (54%), visuomotor integration (50%), and speeded information processing (35%). A diagnosis of multiple sclerosis (odds ratio = 3.60, confidence interval = 1.07, 12.36, P = .04) and overall neurologic disability (odds ratio = 1.47, confidence interval = 1.10, 2.10, P = .03) were the only independent predictors of cognitive impairment. Cognitive impairment may occur early in these patients, and prompt recognition is critical for their care.

Cognitive and behavioural comorbidities are often seen in children with epilepsy, and are more common and severe in refractory epilepsy. These comorbidities are associated with worse quality of life, increased behavioural and language problems and worse social skills, all of which adversely affect long-term psychosocial functioning. To enable early intervention and therapy, children and teens with epilepsy should be periodically screened for cognitive comorbidities. The location of the epileptic focus can, to a certain degree, predict the type(s) of comorbidity; however, the spectrum of disability is often broad, presumably because focal perturbations can cause network dysfunction. Comorbidities often result from underlying structural or functional pathology that has led to seizures. In selected cases, therapy targeting the underlying cause, such as the ketogenic diet for GLUT1 deficiency syndromes, may be remarkably effective in ameliorating both seizures and cognitive concerns. In many cases, however, cognitive impairment persists despite seizure control. In epileptic encephalopathies, frequent seizures and/or interictal epileptiform abnormalities exacerbate neurocognitive dysfunction, owing to synaptic reorganization or impaired neurogenesis, or to other effects on developing neural circuits, and prompt initiation of effective antiepileptic therapy is essential to limit cognitive comorbidities.

There is increasing evidence that exposure of developing brains in animals, including nonhuman primates, to commonly-utilized anesthetic agents may cause adverse effects on cognition and behavior. In this paper, we summarize our methodology for a population-based, propensity-matched study to evaluate possible anesthesia-related sequelae in preschool children when evaluated in elementary or high school. A cohort of all children born in Olmsted County, Minnesota between the years 1994-2007 who are currently local residents has been identified. Existing medical records are being used to identify all episodes of exposure to general anesthesia prior to the age of 3 years (i.e., prior to their 3rd birthday). Children with multiple, single, and no anesthesia exposure are sampled for testing between the ages of 8-12 years or 15-19 years during the period 2012-2016. To match children in different exposure groups as closely as possible, sampling is guided by propensity-matching for the likelihood of receiving anesthesia. Selected children are invited to participate in a single 4-hour session of neuropsychological testing, including the National Center for Toxicological Research-Operant Test Battery, which has been used to study anesthetic neurotoxicity in nonhuman primates. The results of this testing will be compared among children with different anesthetic exposure histories. The expected products of this research will be a detailed phenotype of possible anesthetic-associated neurotoxicity in humans, utilizing a robust patient database and neuropsychological testing battery, and the first comparison of effects of anesthetic exposure in children and nonhuman primates performing nearly identical behavioral tasks.

Background: Whether exposure to a single general anaesthetic (GA) in early childhood causes long-term neurodevelopmental problems remains unclear. Methods: PubMed/MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Library were searched from inception to October 2019. Studies evaluating neurodevelopmental outcomes and prospectively enrolling children exposed to a single GA procedure compared with unexposed children were identified. Outcomes common to at least three studies were evaluated using random-effects meta-analyses. Results: Full-scale intelligence quotient (FSIQ); the parentally reported Child Behavior Checklist (CBCL) total, externalising, and internalising problems scores; and Behavior Rating Inventory of Executive Function (BRIEF) scores were assessed. Of 1644 children identified, 841 who had a single exposure to GA were evaluated. The CBCL problem scores were significantly higher (i.e. worse) in exposed children: mean score difference (CBCL total: 2.3 [95% confidence interval {CI}: 1.0e3.7], P¼0.001; CBCL externalising: 1.9 [95% CI: 0.7e3.1], P¼0.003; and CBCL internalising problems: 2.2 [95% CI: 0.9e3.5], P¼0.001). Differences in BRIEF were not significant after multiple comparison adjustment. Full-scale intelligence quotient was not affected by GA exposure. Secondary analyses evaluating the risk of these scores exceeding predetermined clinical thresholds found that GA exposure was associated with increased risk of CBCL internalising behavioural deficit (risk ratio [RR]: 1.47; 95% CI: 1.08e2.02; P¼0.016) and impaired BRIEF executive function (RR: 1.68; 95% CI: 1.23e2.30; P¼0.001). Conclusions: Combining results of studies utilising prospectively collected outcomes showed that a single GA exposure was associated with statistically significant increases in parent reports of behavioural problems with no difference in general intelligence.

Background: We hypothesised that exposure to multiple, but not single, procedures requiring general anaesthesia before age 3 yr is associated with a specific pattern of deficits in processing speed and fine motor skills. Methods: A secondary analysis (using factor and cluster analyses) of data from the Mayo Anesthesia Safety in Kids study was conducted, in which unexposed, singly exposed, and multiply exposed children born in Olmsted County, MN, USA from 1994 to 2007 were sampled using a propensity-guided approach and underwent neuropsychological testing at ages 8e12 or 15e20 yr. Results: In the factor analysis, the data were well fit to a five factor model. For subjects multiply (but not singly) exposed to anaesthesia, a factor reflecting motor skills, visual-motor integration, and processing speed was significantly lower [standardised difference of e0.35 (95% confidence interval {CI} e0.57 to e0.13)] compared with unexposed subjects. No other factor was associated with exposure. Three groups were identified in the cluster analysis, with 106 subjects (10.6%) in Cluster A (lowest performance in most tests), 557 (55.9%) in Cluster B, and 334 (33.5%) in Cluster C (highest performance in most tests). The odds of multiply exposed children belonging to Cluster A was 2.83 (95% CI: 1.49e5.35; P¼0.001) compared with belonging to Cluster B; there was no other significant association between exposure status and cluster membership. Conclusions: Multiple, but not single, exposures to procedures requiring general anaesthesia before age 3 yr are associated with a specific pattern of deficits in neuropsychological tests. Factors predicting which children develop the most pronounced deficits remain unknown.

IMPORTANCE There are limited data on the racial disparities in the incidence of attention-deficit/ hyperactivity disorder (ADHD) diagnosis in children at the national level. OBJECTIVE To explore differences in rates of diagnosis of ADHD and use of treatment among children by race and ethnicity. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study assessed insurance claims data of children born in the US between January 1, 2006, and December 31, 2012, who had continuous insurance coverage for at least 4 years. The last date of follow-up included in the cohort was June 30, 2019. Race/ethnicity designations were based on self-report and included non-Hispanic White, Black, Hispanic, and Asian. Data were analyzed between October 2019 and December 2020. EXPOSURES Race and ethnicity. MAIN OUTCOMES AND MEASURES ADHD diagnosis as defined by International Classification of Diseases codes (ninth or tenth editions) and treatment within 1 year of diagnosis, including medication and behavior therapy as defined by billing codes. Data on ADHD diagnosis and treatment were adjusted for sex, region, and household income in a multivariate Cox regression model. RESULTS Among 238 011 children in the cohort (116 093 [48.8%] girls; 15 183 [6.7%] Asian, 14 792 [6.2%] Black, 23 358 [9.8%] Hispanic, and 173 082 [72.7%] White children), 11 401 (4.8%) were diagnosed with ADHD. The cumulative incidence at age 12 was 13.12% (95% CI, 12.79%-13.46%). In multivariate Cox regression adjusting for sex, region, and household income, the hazard ratio for Asian children was 0.48 (95% CI, 0.43-0.53); Black children, 0.83 (95% CI, 0.77-0.90); and Hispanic children, 0.77 (95% CI, 0.72, 0.82) compared with White children. In the first year after diagnosis, 516 preschool children (19.4%) received behavioral therapy only, 860 (32.4%) had medications only, 505 (19.0%) had both, and 774 (29.2%) had no claims associated with either option. A higher percentage of school-aged children (2904 [65.6%]) were prescribed medications, and fewer had therapy only (639 [14.4%]) or no treatment at all (884 [20.0%]). Compared with other groups, White children were more likely to receive some kind of treatment. Asian children had the highest odds of receiving no treatment (odds ratio compared with White children, 0.54; 95% CI, 0.42-0.70). CONCLUSIONS AND RELEVANCE Racial and ethnic disparities in the diagnosis and treatment of ADHD are evident. Future study is needed to elucidate the mechanism behind these disparities, with special attention to Asian children. Clinicians should provide racially sensitive care in the evaluation and treatment of ADHD.