Cognitive Function in Genetic Generalized Epilepsies: Insights From Neuropsychology and Neuroimaging

Abstract

Genetic generalized epilepsies (GGE), previously called idiopathic generalized epilepsies, constitute about 20% of all epilepsies, and include childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone (CAE, JAE, JME, and GGE-GTCS, respectively). GGE are characterized by high heritability, likely underlain by polygenetic mechanisms, which may relate to atypical neurodevelopmental trajectories. Age of onset ranges from preschool years, for CAE, to early adulthood for GGE-GTCS. Traditionally, GGE have been considered benign, a belief contrary to evidence from neuropsychology studies conducted over the last two decades. In JME, deficits in executive and social functioning are common findings and relate to impaired frontal lobe function. Studies using neuropsychological measures and cognitive imaging paradigms provide evidence for hyperconnectivity between prefrontal and motor cortices, aberrant fronto-thalamo-cortical connectivity, and reduced fronto-cortical and subcortical gray matter volumes, which are associated with altered cognitive performance. Recent research has also identified associations between abnormal hippocampal morphometry and fronto-temporal activation during episodic memory. Longitudinal studies on individuals with newly diagnosed JME have observed cortical dysmaturation, which is paralleled by delayed cognitive development compared to the patients' peers. Comorbidities and cognitive deficits observed in other GGE subtypes, such as visuo-spatial and language deficits in both CAE and JAE, have also been correlated with atypical neurodevelopment. Although it remains unclear whether cognitive impairment profiles differ amongst GGE subtypes, effects may become more pronounced with disease duration, particularly in absence epilepsies. Finally, there is substantial evidence that patients with JME and their unaffected siblings share patterns of cognitive deficits, which is indicative of an underlying genetic etiology (endophenotype), independent of seizures and anti-epileptic medication.

Disorganization of language and working memory systems in frontal versus temporal lobe epilepsy

“…Participants underwent standardized neuropsychological tests 46 providing measures of general intellectual level (IQ), working memory, letter and category fluency, naming, psychomotor speed and executive function (mental flexibility), verbal and visuo-spatial learning and recall. Verbal reasoning and comprehension scores were available for patient groups.…”

Reflex Epilepsy

“…The four specific IGEs are: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and generalized tonic-clonic seizures (GTCS) alone [12]. CAE occurs in childhood, is twice as common in females, and has peak onset between 4-7 years of age [13]. It is characterized by brief unprovoked absence seizures, with abrupt onset and cessation, and impairment of consciousness with no post-ictal symptoms [12].…”

“…It can be induced by hyperventilation, and physical examination is otherwise normal. JAE peak age of onset is between 9 and 13 and occurs evenly in males and females [13]. In JAE, predominant seizure type is absence, which typically occurs many times per day, but much less frequently than in CAE.…”

Assessment of higher mental functions in patients with idiopathic (genetic) generalized epilepsies

“…в своем исследовании также подчеркивают, что у детей с пикнолепсией имеется паттерн нейрокогнитивных нарушений, связанный с лобными функциями (дефицит управляющих функций, интеллектуальной гибкости, нарушения внимания), что в результате формирует типичный нейропсихологический профиль пациентов с детской абсансной эпилепсией [25]. Проблемы с иными функциями (пространственное восприятие, обработка речевой информации, кинестетический гнозис) либо вовсе не выявляются [25,31], либо же, напротив, выявляются системно, причем значительные [2,32], из чего можно сделать вывод о крайней неоднородности результатов и необходимости продолжения исследований в указанной области с более однотипными методологическими подходами к оценке.…”

“…С одной стороны, это важно для понимания точной клинической картины указанных форм эпилепсий и фенотипических особенностей больных, с другой стороны, осведомленность о наличии проблем с высшими психическими функциями необходима для выстраивания траектории в образовании и профессиональной ориентации пациентов. Традиционно считается, что влияние самого заболевания на когнитивные способности при идиопатических формах минимально [2]. Тем не менее сообщается о страдании высших психических функций при данных видах эпилепсии.…”