Inhibiting Epileptiform Activity in Cognitive Disorders: Possibilities for a Novel Therapeutic Approach

Abstract

Cognitive impairment is a common and seriously debilitating symptom of various mental and neurological disorders including autism, attention deficit hyperactivity disorder, multiple sclerosis, epilepsy, and neurodegenerative diseases, like Alzheimer's disease. In these conditions, high prevalence of epileptiform activity emerges as a common pathophysiological hallmark. Growing body of evidence suggests that this discrete but abnormal activity might have a long-term negative impact on cognitive performance due to neuronal circuitries' remodeling, altered sleep structure, pathological hippocampocortical coupling, and even progressive neuronal loss. In animal models, epileptiform activity was shown to enhance the formation of pathological amyloid and tau proteins that in turn trigger network hyperexcitability. Abolishing epileptiform discharges might slow down the cognitive deterioration. These findings might provide basis for therapeutic use of antiepileptic drugs in neurodegenerative cognitive disorders. The aim of our review is to describe the data on the prevalence of epileptiform activity in various cognitive disorders, to summarize the current knowledge of the mechanisms of epileptic activity in relation to cognitive impairment, and to explore the utility of antiepileptic drugs in the therapy of cognitive disorders. We also propose future directions for drug development and novel therapeutic interventions targeting epileptiform discharges in these disorders.

Electroencephalographic Correlates of Cognition among Nigerian Women with Epilepsy on Anti-epileptic Monotherapy

“…[6] Newer AEDs have more selective targets modulating excitability in discreet neuronal circuits and are better positioned for the potential treatment of interictal epileptiform discharges associated with cognitive impairment. [28] The finding from the present study revealed that LEV performed better on assessing memory domain and overall global cognitive function. This is in tandem with many animal and clinical studies showing the cognitive enhancing effect of LEV, a function it was initially developed for from Piracetam.…”

“…An unexplored therapeutic potential in treating cognitive disorders might be the modulation of epileptiform discharges and neuronal excitability. [28] Therefore, it is reasonable to consider the role of AEDs in controlling neuronal toxicity and epileptiform discharges associated with cognitive impairment.…”

The Significance of Subclinical Epileptiform Activity in Alzheimer's Disease: A Review

“…Novel observations started to draw more attention to SEA since increased incidence is detected consistently in diseases affecting cognitive functions, including AD ( 42 ). Based on recent reviews, the leading research sites agree that SEA is a characteristic EEG hallmark of AD-related cortical hyperexcitability ( 10 , 42 – 45 ).…”

“…Novel observations started to draw more attention to SEA since increased incidence is detected consistently in diseases affecting cognitive functions, including AD ( 42 ). Based on recent reviews, the leading research sites agree that SEA is a characteristic EEG hallmark of AD-related cortical hyperexcitability ( 10 , 42 – 45 ). It seems also feasible that the imbalance between excitatory and inhibitory regulation propagates from the dentate gyrus to the hippocampus and later to cortical structures explaining the dominant occurrence of SEA in the temporal regions ( 43 ).…”

“…The strongest synchrony among neuron populations is achieved during slow-wave sleep ( 46 ), possibly explaining the increased occurrence of SEA in deep sleep. Its pathologic role in AD is postulated by numerous reports suggesting that hyperexcitability might lead to increased neurodegeneration due to excitotoxicity, it changes the long-distance neural network connections and disrupts sleep-related memory consolidation ( 42 ). These concepts are supported by two of the reviewed studies demonstrating that appearance of SEA is not benign since it associates with increased progression of cognitive decline ( 12 , 13 ) and with lower cognitive functioning ( 13 ) and there is a clear correlation between the higher number of discharges and faster disease progression ( 13 ).…”