Understanding neurodevelopmental trajectories and behavioral profiles in SCN1A-related epilepsy syndromes.

BACKGROUND: A pathogenic variant in SCN1A can result in a spectrum of phenotypes, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS + ) syndrome. Dravet syndrome (DS) is associated with refractory seizures, developmental delay, intellectual disability (ID), motor impairment, and challenging behavior(1,2). GEFS + is a less severe phenotype in which cognition is often normal and seizures are less severe. Challenging behavior largely affects quality of life of patients and their families. This study describes the profile and course of the behavioral phenotype in patients with SCN1A-related epilepsy syndromes, explores correlations between behavioral difficulties and potential risk factors. METHODS: Data were collected from questionnaires, medical records, and semi-structured interviews. Behavior difficulties were measured using the Adult/Child Behavior Checklist (C/ABCL) and Adult self-report (ASR). Other questionnaires included the Pediatric Quality of Life Inventory (PedsQL), the Functional Mobility Scale (FMS) and the Sleep Behavior Questionnaire by Simonds & Parraga (SQ-SP). To determine differences in behavioral difficulties longitudinally, paired T-tests were used. Pearson correlation and Spearman rank test were used in correlation analyses and multivariable regression analyses were employed to identify potential risk factors. RESULTS: A cohort of 147 participants, including 107 participants with DS and 40 with genetic epilepsy with febrile seizures plus (GEFS + ), was evaluated. Forty-six DS participants (43.0 %) and three GEFS + participants (7.5 %) showed behavioral problems in the clinical range on the A/CBCL total problems scale. The behavioral profile in DS exists out of withdrawn behavior, aggressive behavior, and attention problems. In DS patients, sleep disturbances (ß = 1.15, p < 0.001) and a lower age (ß = -0.21, p = 0.001) were significantly associated with behavioral difficulties. Between 2015 and 2022, behavioral difficulties significantly decreased with age (t = -2.24, CI = -6.10 - -0.15, p = 0.04) in DS participants aging from adolescence into adulthood. A decrease in intellectual functioning (ß = 3.37, p = 0.02) and using less antiseizure medications in 2022 than in 2015, (ß = -1.96, p = 0.04), were identified as possible risk factors for developing (more) behavioral difficulties. CONCLUSIONS: These findings suggest that, in addition to epilepsy, behavioral difficulties are a core feature of the DS phenotype. Behavioral problems require personalized management and treatment strategies. Further research is needed to identify effective interventions.

Chronic kidney disease and cognitive decline in patients with type 2 diabetes at elevated cardiovascular risk.

AIMS: We addressed the question whether chronic kidney disease (CKD) may contribute to cognitive decline in type 2 diabetes. METHODS: Participants with type 2 diabetes with elevated cardiovascular risk or CKD from cognition substudies of two large trials were studied prospectively (CARMELINA: n = 2666, mean ± SD age 68.1 ± 8.7 years, CAROLINA: n = 4296; 64.7 ± 9.4 years). Estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) at baseline were related to cognitive performance (Mini-Mental State Examination (MMSE) and attention and executive functioning score (A&E)) in linear regression analyses, adjusted for demographics, cardiovascular risk factors and treatment, at baseline and follow-up. RESULTS: CKD at baseline was more common in CARMELINA than CAROLINA (eGFR<60 in 72.6 % and 19.6 %, macroalbuminuria in 35.0 % and 4.1 %, respectively). Baseline eGFR was related to A&E in CARMELINA (b = 0.02 per 10 ml/min/1.73m2, 95%CI [0.01,0.03]). Baseline UACR was related to A&E in CAROLINA (b = -0.01 per doubling of UACR mg/g, 95%CI [-0.02,-0.002]). Baseline UACR predicted decline in A&E in CAROLINA (median 6.1 years follow-up; b = -0.01, 95%CI [-0.03,-0.0001] per doubling of UACR mg/g). CONCLUSIONS: eGFR and UACR were associated with A&E in two cohorts with type 2 diabetes, enriched for CKD and cardiovascular disease. The small effect size estimates indicate limited impact of kidney dysfunction on cognition in this setting. GOV IDENTIFIERS: NCT01897532 NCT01243424.