Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture.

OBJECTIVE: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE. METHODS: We studied 134 families with ≥ 2 first or second-degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. RESULTS: The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13-28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug-resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed. INTERPRETATION: FMTLE is a generally mild drug-responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub-genome-wide significant focal epilepsy genome-wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023;94:825-835.

Evaluation of left-turn lane offset using the naturalistic driving study data.

INTRODUCTION: The Strategic Highway Research Program 2 (SHRP 2) Naturalistic Driving Study (NDS) data were used to evaluate gap acceptance behavior of drivers at left-turn lanes with negative, zero, or positive offsets ranging from -29 ft to +6 ft. The objectives of the study were to develop guidance for the design of offset left-turn lanes used as a safety countermeasure, and to provide insight regarding the use of the NDS data to future users. METHOD: The study included 3350 gaps in opposing traffic evaluated by 145 NDS volunteer drivers and 275 non-NDS drivers at 14 two-way stop-controlled intersections and 44 signalized opposing left-turn pairs. Logistic regression was used to model the critical gap length for drivers as a function of offset, under conditions when their view was either blocked or not by an opposing left-turning driver. RESULTS: The analysis found that the critical gap was longer at left-turn lanes with negative offsets than at those with zero or positive offsets, and was also longer when sight distance was blocked by an opposing left-turning vehicle. Sight distance was much more likely to be restricted by an opposing left-turning vehicle at negative-offset and drivers at those intersections were less likely to accept a gap when an opposing left-turn driver was present. CONCLUSIONS: Longer gap lengths could potentially result in decreased operational efficiency of an intersection. In addition, drivers making left-turns at negative-offset left-turn lanes are, on average, more likely to leave the shortest amount of time between their turn and the arrival of the next opposing through-vehicle, which may present a potential safety concern. PRACTICAL APPLICATIONS: The findings provide guidance for highway designers considering using offset left-turn lanes as a crash countermeasure. This research also highlights the benefits and limitations of using the SHRP 2 NDS data to answer similar research questions.