Development and Validation of Prediction Models for Developmental and Intellectual Outcome Following Pediatric Epilepsy Surgery

Background and Objectives:To (1) identify predictors of postoperative intelligence and developmental quotients (IQ/DQ) and (2) develop and validate clinically applicable IQ/DQ prediction models.Methods:We retrospectively analyzed neuropsychological outcomes and their possible determinants for children treated in Bethel and Utrecht since 1990. We performed separate analyses for patients with IQ and those with only DQ available. We developed prediction models based on presurgical determinants to predict dichotomized levels of performance (IQ≥85, IQ≥70, DQ≥50).Results:IQ/DQ data before and two years after surgery were available for 492 patients (IQ n=365, DQ n=127). At a cutoff-level ±10 points, the chance of improvement was considerably higher than the chance of deterioration (IQ 37.3% vs. 6.6% and DQ 31.5% vs. 15.0%, respectively). Presurgical IQ/DQ was the strongest predictor of postoperative cognition (IQ r=0.85, p<.001, DQ: r=0.57, p<.001).Two IQ models were developed in the Bethel cohort (n=258) and externally validated in the Utrecht cohort (n=102). For DQ, we developed the model in the Bethel cohort and used 10-fold cross-validation. Models allowed good prediction at all three cutoff-levels (correct classification for IQ≥85=86%, IQ≥70=91%, DQ≥50=76%). External validation of the IQ models showed high accuracy (IQ≥85: 0.82, CI 0.75-0.91, IQ≥70: 0.84, CI 0.77-0.92) and excellent discrimination (ROC curves IQ≥85: AUC 0.90, CI 0.84-0.96; IQ≥70: AUC 0.92, CI 0.87-0.97).Discussion:After epilepsy surgery in children, the risk of cognitive deterioration is very low. Presurgical development has a strong impact on the postoperative trajectory. The presented models can improve presurgical counseling of patients and parents by reliably predicting cognitive outcomes.Classification of Evidence:This study provides Class II evidence that for children undergoing epilepsy surgery presurgical IQ/DQ was the strongest predictor of postoperative cognition.

Ukrainian Studies Direction in the Cultural and Scholarly Activity of the Ukrainian Military Emigration of the 20th-Century Interwar Period

The purpose of this article is to investigate the specifics of Ukrainian studies in the cultural and scholarly activities of the Ukrainian military emigration. Based on its archival documents and research publications, such issues are covered: the origins of cultural and scholarly activities of the Ukrainian military emigration in view of its internment in 1920–1921; the place of the Ukrainian studies direction in the activities of scientific military societies and respective museum departments; Ukrainian studies aspects concerned by the representatives of the Ukrainian military emigration in their scientific works.The research process provided such results: the cultural and scientific activities of the Ukrainian military emigration stemmed from the work of the Military Section of the Ukrainian Diplomatic Mission and cultural and educational commissions, which provided camp soldiers with lectures on Ukrainian studies, literary and theatrical arts, and library work. The activities of scientific military societies and museum departments presented the direction of Ukrainian studies in the collection of archival documents and materials on the National Liberation War of 1917–1921, publication of thematic editions, lectures on Ukrainian history, and participation in ceremonial and memorial events, which were conducted in the academic environment of the Ukrainian emigration. In their research works, representatives of the Ukrainian military emigration touched upon aspects of the history of Ukraine during the National Liberation War of 1917–1921, the Cossacks, Ukrainian ethnography and geography. They managed to have accumulated significant intellectual outcome in the field of Ukrainian studies, which is still relevant today. The achievement of the author of the study is a synthesis created on the basis of a comprehensive study of sources and historiography, which consider the problem of Ukrainian military emigration in the interwar period in the light of Ukrainian studies, which is quite unusual for the respective field of domestic historiography. This made it possible to obtain new conclusions.

Methylphenidate-induced psychosis in a young antipsychotic-naïve female patient

Methylphenidate (MPD) is commonly prescribed for patients with Attention Deficit/Hyperactivity Disorder (ADHD). Although used off-label, MPD forms part of complex and multifactorial treatment regimen for narcolepsy and hypersomnia, together with including behavioural interventions. The drug is sometimes also prescribed off-label to subjects with other mental illness or somatic condition to improve intellectual outcome, ease fatigue or enhance the ability to concentrate. Common side effects include headache, insomnia, decreased appetite and hypertension. Concurrently, clinicians should be aware of relatively rare but potentially threatening adverse effects including agitation and psychotic symptoms. Several case reports regarding MPD-induced psychosis have been published, but most of them regard children or teenagers (1) and much less is known about drug-induced psychosis in adults (2). In this article, we present a case report of MPD-induced psychosis in a 31-year-old, antipsychotic-naïve patient. Careful evaluation including clinical examination, medical and family history and possible early signs of psychosis is recommended each time before MPD treatment will be initiated.

Digital Communication Tools and Knowledge Creation Processes for Enriched Intellectual Outcome—Experience of Short-Term E-Learning Courses during Pandemic

Social isolation during the pandemic contributed to the transition of educational processes to e-learning. A short-term e-marketing education program for a variety of students was introduced in May 2020 and is taught entirely online. A survey was conducted regularly in the last week of training using Google Forms, and three cohorts were surveyed in July, September, and December 2020. A high level of satisfaction indicates an interest in the content and a positive assessment of the level of comfort of an organization adapted to the needs of students; this positive result contrasted with the negative opinion of the remote learning in Russia since March 2020, and this surprising satisfaction of students has motivated the study to try to explain its reasons. This result was compared with the short-term course taught through the educational pedagogical platform of a university. The students of traditional short- and long-term university programs were asked to assess their satisfaction with different digital communication tools used for e-learning. They showed low satisfaction with the pedagogical platform and a positive reaction to the e-communication tools (messengers, social media, short surveys, video conferences, etc.). The qualitative responses helped to better understand the real problems of the cognitive process and the triple structure of intellectual production during e-learning, including interest in the intellectual outcome, the need for emotional and motivational elements of cooperation and competition between students, and smooth behavioral enrichment, which requires special efforts from students and their leading from teachers. The main conclusion concerns a practical decision to continue the implementation of the educational program in the form of an online course with the use of the mixed digital communication tools of social media, messengers, and video conferences, which most likely meets the expectations and capabilities of students.

Genotype-phenotype correlations in patients with de novo KCNQ2 pathogenic variants

ObjectiveEarly identification of de novo KCNQ2 variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo KCNQ2 pathogenic variants to dissect genotype-phenotype correlations.MethodsPatients with de novo KCNQ2 pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants.ResultsWe included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome.A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome.ConclusionsWe highlight the complexity of variant interpretation to assess the impact of a class of de novo KCNQ2 mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.

MANAGEMENT OF ENDOCRINE DISEASE Subclinical hypothyroidism in children

Subclinical hypothyroidism (SH) is biochemically defined as serum TSH levels above the upper limit of the reference range in the presence of normal free T4 (FT4) concentrations. While there is a general agreement to treat subjects with serum TSH levels above 10 mU/L, the management of mild form (TSH concentrations between 4.5 and 10 mU/L) is still a matter of debate. In children, mild SH is often a benign and remitting condition and the risk of progression to overt thyroid dysfunction depends on the underlying condition, being higher in the autoimmune forms. The major concern is to establish whether SH in children should always be considered an expression of mild thyroid dysfunction and may deserve treatment. Current data indicate that children with mild SH have normal linear growth, bone health and intellectual outcome. However, slight metabolic abnormalities and subtle deficits in specific cognitive domains have been reported in children with modest elevation of TSH concentration. Although these findings are not sufficient to recommend levothyroxine treatment for all children with mild SH, they indicate the need for regular monitoring to ensure early identification of children who may benefit from treatment. In the meanwhile, the decision to initiate therapy in children with mild SH should be based on individual factors.

Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was &lt;85 in 62%. Movement disorders were found in 17 (47%) of the 36 tested patients. In females aged 12 years and older, primary ovarian insufficiency was diagnosed in 12 (71%) of the 17 patients. Significant differences in N-glycan peaks were found between controls and patients. However, no significant differences in either N-glycans or galactose-1-phosphate levels were found between patients with a poor (intellectual outcome &lt; 85) and normal intellectual outcome (intellectual outcome ≥ 85), and with or without movement disorders or primary ovarian insufficiency. The variant patients detected by newborn screening, with previously unknown geno- and phenotypes and currently no long-term complications, demonstrated significantly lower galactose-1-phospate levels than classical patients (P &lt; 0.0005). Qualitative analysis of the MRI’s demonstrated brain abnormalities in 18 of the 21 patients, more severely in patients with a lower intellectual outcome and/or with movement disorders. This study demonstrates a large variability in clinical outcome, which varies from a below average intelligence, movement disorders and in females primary ovarian insufficiency to a normal clinical outcome. In our cohort of classical galactosemia patients, galactose-1-phosphate levels and N-glycan variations were not associated with clinical outcomes, but galactose-1-phosphate levels did differentiate between classical and variant patients detected by newborn screening. The correlation between brain abnormalities and clinical outcome should be further investigated by quantitative analysis of the MR images. The variability in clinical outcome necessitates individual and standardized evaluation of all classical galactosemia patients.