Abstract
Children with epilepsy often present with pervasive cognitive and behavioral comorbidities including working memory impairments, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder. These non-seizure characteristics are severely detrimental to overall quality of life. Some of these children, particularly those with epilepsies classified as Landau-Kleffner Syndrome or continuous spike and wave during sleep, have infrequent seizure activity but frequent focal epileptiform activity. This frequent epileptiform activity is thought to be detrimental to cognitive development; however, it is also possible that these IIS events initiate pathophysiological pathways in the developing brain that may be independently associated with cognitive deficits. These hypotheses are difficult to address due to the previous lack of an appropriate animal model. To this end, we have recently developed a rat model to test the role of frequent focal epileptiform activity in the prefrontal cortex. Using microinjections of a GABAA antagonist (bicuculline methiodine) delivered multiple times per day from postnatal day (p) 21 to p25, we showed that rat pups experiencing frequent, focal, recurrent epileptiform activity in the form of interictal spikes during neurodevelopment have significant long-term deficits in attention and sociability that persist into adulthood. To determine if treatment with ACTH, a drug widely used to treat early-life seizures, altered outcome we administered ACTH once per day subcutaneously during the time of the induced interictal spike activity. We show a modest amelioration of the attention deficit seen in animals with a history of early life interictal spikes with ACTH, in the absence of alteration of interictal spike activity. These results suggest that pharmacological intervention that is not targeted to the interictal spike activity is worthy of future study as it may be beneficial for preventing or ameliorating adverse cognitive outcomes.
Highlights
It is widely believed that frequent epileptiform events seen in children with epilepsy are capable of causing deleterious alterations in developing brain networks and are associated with the high incidence of cognitive deficits and psychiatric comorbidities in these patients [1,2]
This experimental model of early life interictal spikes (IIS) was developed to assess the effect of focal inhibitory/excitatory imbalance resulting in IIS activity on cognition in order to (1) control for secondary effects of IIS on the prefrontal cortex (PFC) through connections from other brain regions (2) control for global brain injury incurred during generalized seizures
We have examined the role of adrenocorticotrophic hormone (ACTH) treatment on IIS-associated deficits in behavior and found a modest but significant decrease in the number of omissions made during a delayed non-match to sample (DNMS) task, suggesting ACTH may have a role in improving an attention deficit associated with early life epileptiform activity
Summary
It is widely believed that frequent epileptiform events seen in children with epilepsy are capable of causing deleterious alterations in developing brain networks and are associated with the high incidence of cognitive deficits and psychiatric comorbidities in these patients [1,2]. It has been suggested that when the EEG is normalized, these impairments are often reduced or eliminated [3,4] This line of thinking has led to the idea that, like overt seizures, EEG interictal discharges should be treated [5]. It is unknown if the epileptiform activity itself, some downstream consequence of the epileptiform activity, or a combination of both of these mechanisms negatively impacts cognition in the developing brain. We hypothesized that pharmacological treatment could improve the IIS activity and that this treatment could ameliorate these associated behavioral deficits
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
