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Abstract
Juvenile myoclonic epilepsy is the most common genetic generalized epilepsy syndrome, characterized by a complex polygenetic aetiology. Structural and functional MRI studies demonstrated mesial or lateral frontal cortical derangements and impaired fronto-cortico-subcortical connectivity in patients and their unaffected siblings. The presence of hippocampal abnormalities and associated memory deficits is controversial, and functional MRI studies in juvenile myoclonic epilepsy have not tested hippocampal activation. In this observational study, we implemented multi-modal MRI and neuropsychological data to investigate hippocampal structure and function in 37 patients with juvenile myoclonic epilepsy, 16 unaffected siblings and 20 healthy controls, comparable for age, gender, handedness and hemispheric dominance as assessed with language laterality indices. Automated hippocampal volumetry was complemented by validated qualitative and quantitative morphological criteria to detect hippocampal malrotation, assumed to represent a neurodevelopmental marker. Neuropsychological measures of verbal and visuo-spatial learning and an event-related verbal and visual memory functional MRI paradigm addressed mesiotemporal function. We detected a reduction of mean left hippocampal volume in patients and their siblings compared with controls (P < 0.01). Unilateral or bilateral hippocampal malrotation was identified in 51% of patients and 50% of siblings, against 15% of controls (P < 0.05). For bilateral hippocampi, quantitative markers of verticalization had significantly larger values in patients and siblings compared with controls (P < 0.05). In the patient subgroup, there was no relationship between structural measures and age at disease onset or degree of seizure control. No overt impairment of verbal and visual memory was identified with neuropsychological tests. Functional mapping highlighted atypical patterns of hippocampal activation, pointing to abnormal recruitment during verbal encoding in patients and their siblings [P < 0.05, familywise error (FWE)-corrected]. Subgroup analyses indicated distinct profiles of hypoactivation along the hippocampal long axis in juvenile myoclonic epilepsy patients with and without malrotation; patients with malrotation also exhibited reduced frontal recruitment for verbal memory, and more pronounced left posterior hippocampal involvement for visual memory. Linear models across the entire study cohort indicated significant associations between morphological markers of hippocampal positioning and hippocampal activation for verbal items (all P < 0.05, FWE-corrected). We demonstrate abnormalities of hippocampal volume, shape and positioning in patients with juvenile myoclonic epilepsy and their siblings, which are associated with reorganization of function and imply an underlying neurodevelopmental mechanism with expression during the prenatal stage. Co-segregation of abnormal hippocampal morphology in patients and their siblings is suggestive of a genetic imaging phenotype, independent of disease activity, and can be construed as a novel endophenotype of juvenile myoclonic epilepsy.
Highlights
Juvenile myoclonic epilepsy (JME) is a highly prevalent genetic generalized epilepsy syndrome, accounting for up to 10% of all epilepsies (Camfield et al, 2013; Scheffer et al, 2017)
Subtle abnormalities include atypical appearance and positioning of the hippocampal formation, with rounded or pyramidal shape and abnormal collateral or occipito-temporal sulcal morphometry, an entity known as hippocampal malrotation (HIMAL) (Bernasconi et al, 2005; Tsai et al, 2016)
Our findings provide novel insights into the structural neural correlates of the genetic risk for JME, suggesting the involvement of regions beyond the classically implicated fronto-cortical networks
Summary
Juvenile myoclonic epilepsy (JME) is a highly prevalent genetic generalized epilepsy syndrome, accounting for up to 10% of all epilepsies (Camfield et al, 2013; Scheffer et al, 2017). Neuropsychological evaluations in JME have shown frontal lobe dysfunction, with impaired performance during working memory, prospective memory, decisionmaking and other executive tasks (Sonmez et al, 2004; Wandschneider et al, 2012; Zamarian et al, 2013; Wolf et al, 2015), and specific personality traits (Plattner et al, 2007; de Araujo Filho and Yacubian, 2013). Abnormal fronto-cortico-thalamic connections (Pulsipher et al, 2009; O’Muircheartaigh et al, 2011, 2012) and augmented structural and functional connectivity between motor areas and prefrontal cognitive networks (Vollmar et al, 2011, 2012) have been interpreted as substrates of both ictogenesis and cognitive dysfunction (Koepp, 2005; Wandschneider et al, 2012). While most cognitive and imaging investigations have focused on the frontal lobes, structure and function of temporal lobe areas, the hippocampus, are less well characterized. Subtle abnormalities include atypical appearance and positioning of the hippocampal formation, with rounded or pyramidal shape and abnormal collateral or occipito-temporal sulcal morphometry, an entity known as hippocampal malrotation (HIMAL) (Bernasconi et al, 2005; Tsai et al, 2016)
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