Should every child with epilepsy undergo screening for psychiatric comorbidities?

Purpose: We aimed to build a classification system that uses resting-state (no visible scalp epileptic activity) EEG-based directed functional connectivity values to assign a patient to one of three classes: left TLE (LTLE), right TLE (RTLE) or healthy control. Methods: Twenty LTLE, 20 RTLE and 35 healthy controls underwent resting-state high-density EEG. For each subject, sixty 1-sec epochs free of artifacts or interictal spikes were selected. The source activity was obtained for 82 regions of interest using an individual head model and distributed linear inverse solution. The summed outflow and whole-brain directed functional connectivity were estimated in the theta, alpha and beta frequency bands using Granger-causal modeling. A Random Forest classifier (an ensemble of decision tree classifiers) was then used to assign the subject to one of three classes. The mean classification accuracy was computed with a leave-one-out procedure. We selected a maximum of six connectivity values for classification, using a greedy forward selection algorithm. Finally, three classifiers were built: ‘Control vs. LTLE’, ‘Control vs. RTLE’ and ‘LTLE vs. RTLE’. In the final classification system, a new subject is assigned to the class that was most voted by these three classifiers. Results: The ‘Control vs. RTLE’ classifier achieved an accuracy of 78.2% (sensitivity: 80.0%, specificity 77.2%), ‘Control vs. LTLE’ an accuracy of 83.6% (sensitivity 85.0%, specificity 82.9%) and ‘LTLE vs. RTLE’ an accuracy of 85.0% (sensitivity 85.0%, specificity 85.0%). Combining these classifiers into one system yielded that 16, 15 and 27 subjects were correctly classified as being, respectively, RTLE, LTLE and control. Conclusion: The high accuracy achieved demonstrates the potential of resting-state EEG-based directed functional connectivity for the diagnosis and lateralization of TLE. This could constitute a new clinical biomarker for surgical candidates and earlier in the course of the disease

<i>GRIN2A</i>-related disorders:genotype and functional consequence predict phenotype

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders

Routine laboratory testing in children referred because of recurrent wheezing and/or asthma not useful, unlike specific allergy testing

Objective. To investigate the usefulness of laboratory testing and thorax radiography in children, referred to the paediatrician for evaluation of recurrent wheezing. Design. Retrospective. Methods. In this study, 158 children referred for recurrent wheezing to a specialized child outpatient clinic of the Medisch Centrum Leeuwarden, the Netherlands, in the period 1 Januari 1994-31 December 1996, were evaluated according to a routine protocol including haemoglobin, ESR, leucocytes, immunoglobulins, sweat chloride levels and allergy testing and chest roentgenograms. It was determined whether these investigations had yielded abnormal results and whether these test results aided in confirming/rejecting the diagnosis of asthma or were helpful in clinical management. Results. In 144 of the 158 (91%) children the diagnosis 'asthma' or 'recurrent wheezing' was made. Although numerous test results were abnormal they were not helpful in establishing the diagnosis. In only one child an abnormal chest radiograph was helpful (the radiograph showed infiltrative abnormalities). Tests for aero-allergy were rarely positive in children younger than 2 years; in children older than 6 years aero-allergy was found frequently, notably to dust mite (41/144). Conclusion. The results of this study suggest that - except for allergy testing - routine laboratory testing and chest roentgenograms are not indicated in children referred for evaluation of wheezing disorders. Aero-allergy testing may help to decide on preventive measures.</p

Routine laboratory testing in children referred because of recurrent wheezing and/or asthma not useful, unlike specific allergy testing

Objective. To investigate the usefulness of laboratory testing and thorax radiography in children, referred to the paediatrician for evaluation of recurrent wheezing. Design. Retrospective. Methods. In this study, 158 children referred for recurrent wheezing to a specialized child outpatient clinic of the Medisch Centrum Leeuwarden, the Netherlands, in the period 1 Januari 1994-31 December 1996, were evaluated according to a routine protocol including haemoglobin, ESR, leucocytes, immunoglobulins, sweat chloride levels and allergy testing and chest roentgenograms. It was determined whether these investigations had yielded abnormal results and whether these test results aided in confirming/rejecting the diagnosis of asthma or were helpful in clinical management. Results. In 144 of the 158 (91%) children the diagnosis 'asthma' or 'recurrent wheezing' was made. Although numerous test results were abnormal they were not helpful in establishing the diagnosis. In only one child an abnormal chest radiograph was helpful (the radiograph showed infiltrative abnormalities). Tests for aero-allergy were rarely positive in children younger than 2 years; in children older than 6 years aero-allergy was found frequently, notably to dust mite (41/144). Conclusion. The results of this study suggest that - except for allergy testing - routine laboratory testing and chest roentgenograms are not indicated in children referred for evaluation of wheezing disorders. Aero-allergy testing may help to decide on preventive measures.</p