Interictal epileptiform discharges have an independent association with cognitive impairment in children with lesional epilepsy

Abstract

SUMMARYObjectives: The relative contribution of interictal epileptiform discharges (IEDs) to cognitive dysfunction in comparison with the underlying brain pathology is not yet understood in children with lesional focal epilepsy. Methods: The current study investigated the association of IEDs with intellectual functioning in 103 children with medication-resistant focal epilepsy. Hierarchical multiple regression analyses were used to determine the independent contribution of IED features on intellectual functioning, after controlling for effects of lesional pathology, epilepsy duration, and medication. Exploratory analyses were conducted for language and memory scores as well as academic skills available in a subset of participants. Results: The results reveal that IEDs have a negative association with IQ with independent, additive effects documented for frequent and bilaterally distributed IEDs as well as discharge enhancement in sleep. Left-lateralized IEDs had a prominent effect on verbal intelligence, in excess of the influence of left-sided brain pathology. These effects extended to other cognitive functions, most prominently for sleep-enhanced IEDs to be associated with deficits in expressive and receptive language, reading, spelling and numerical skills. Significance: Overall, IED effects on cognition were of a magnitude similar to lesional influences or drug effects (topiramate use). This study demonstrates an association between IEDs and cognitive dysfunction, independent of the underlying focal brain pathology. KEY WORDS: Focal epilepsy, Children, Interictal epileptiform discharges, Cognition, Intelligence. FULL-LENGTH ORIGINAL RESEARCHEarly onset childhood epilepsy is known to be associated with impaired cognitive development, but the relationship of this to ongoing epileptiform activity remains controversial.1 Interictal epileptiform discharges (IEDs) are sharp waves, spikes, or spike-wave complexes that occur in the absence of observable changes in behavior.2 A direct relationship between IED severity and the degree of short-and long-term cognitive impairment experienced by children with epilepsy has been suggested. 3,4 However, the debate continues as to whether IEDs are mainly an expression of the underlying brain pathology, 4,5 a debate that extends to the question of whether pharmacologic suppression of IEDs is warranted. Current evidence on the possible chronic impact of IEDs on cognition in children derives mainly from studies in patients with nonlesional epilepsy and with low seizure frequency. 3,6,7 Across studies in children with benign rolandic epilepsy (BRE), there is evidence that frequent and multifocal IEDs are associated with cognitive deficits, ranging from general intellectual functions 8 and educational progress 3 to affecting only specific cognitive domains. 6,8,9 There is variability in the extent to which IEDs during sleep are associated with cognition, ranging from negative findings 10 to reporting robust effects on reading and verbal IQ (VIQ).11 A large study of children with p...

Response to clobazam in continuous spike‐wave during sleep

“…The present study adds to prior literature because it demonstrates that even small reductions in epileptiform discharges improve language in a relatively short period in a segment of this often significantly disabled population. Our study is concordant with prior studies showing an improvement of epileptiform discharges to treatment and is also concordant in that it shows a benefit in cognitive performance in the language domain . Our study adds to prior literature by demonstrating that a relatively short treatment course can improve cognitive performance.…”

“…In a series of 103 children with medically refractory focal epilepsy, epileptiform discharges were independently associated with worse long‐term cognitive outcomes . Further, epileptiform discharges lateralized to the left hemisphere affected language in excess of the influence of left‐sided brain pathology . Patients with CSWS who undergo surgical resection of an abnormal seizure focus show improvements in cognitive function after surgery .…”

“…There is some evidence suggesting that the underlying etiology is the main determinant of long‐term cognitive outcomes of patients, with epileptiform discharges solely being biomarkers of the underlying etiology . However, there is also evidence that epileptiform discharges are associated with long‐term cognitive dysfunction independent from the underlying etiology . Electrical status epilepticus in sleep (ESES) is one of the most extreme models illustrating the association between epileptiform discharges and cognitive impairment .…”

Does sleep benefit memory consolidation in children with focal epilepsy?

“…This suggests it may be possible to elucidate a threshold below which interictal discharges in sleep have no significant impact on cognition and hence would not warrant treatment. There is evidence that this threshold may lie between spike wave indices of 1 and 10 regardless of underlying etiology, and our current findings are consistent with this.…”

Simulating clinical trials with and without intracranial EEG data

“…It is possible that subclinical discharges have a similar generating mechanism to clinical seizures . Moreover, subclinical discharges appear to have cognitive impacts as well, even when controlling for lesion, drug, and duration of epilepsy . Given the available evidence, we believed it reasonable to allow simulated drugs to have equal efficacy across clinical and subclinical seizures.…”