Epilepsy is among the most prevalent chronic neurological disorders, affecting more than 50 million people worldwide and contributing substantially to the global burden of neurological disease. Beyond the seizures themselves, recurrent epileptic activity is increasingly recognized as a driver of progressive cognitive decline; however, cognitive comorbidity remains under-addressed in routine clinical management. This literature review synthesizes current evidence on the mechanisms, clinical manifestations, and assessment of cognitive impairment associated with recurrent seizures. Recurrent seizures arise from an imbalance between excitatory (glutamate) and inhibitory (GABA) neurotransmission, producing neuronal hyperexcitability and hypersynchronization. During and after seizure episodes, cyclooxygenase-2–dependent cerebral vasoconstriction induces localized hypoperfusion and hypoxia; when repeated, these events accumulate, causing structural and functional brain injury. The hippocampus, essential for memory, is particularly vulnerable to hypoxic-ischemic damage, whereas temporal- and frontal-lobe involvement disrupts memory, language, attention, and executive function. Approximately 60–70% of patients with chronic epilepsy experience cognitive impairment, the severity of which is modulated by age at onset, seizure frequency, duration, and antiepileptic drug use. Practical screening tools such as the Montreal Cognitive Assessment (MoCA), including its validated Indonesian version (MoCA-Ina), demonstrate higher sensitivity than the Mini-Mental State Examination for detecting mild impairment, while brain-derived neurotrophic factor represents a promising biomolecular marker of cognitive dysfunction. Collectively, the evidence indicates that epilepsy management should extend beyond seizure control to incorporate routine cognitive surveillance. Early detection through sensitive screening instruments enables comprehensive, individualized treatment planning and may ultimately improve the long-term quality of life for people living with epilepsy.
The Global Burden of Disease study has identified epilepsy as one of the leading contributors to the global burden of neurological disorders, with more than 50 million people living with epilepsy worldwide. As a chronic brain disorder caused by abnormal neuronal electrical activity, epilepsy is characterized by an enduring predisposition to generate unprovoked seizures, which frequently manifest as recurrent episodes. Recurrent seizures contribute substantially to disability-adjusted life years (DALYs), reflecting the considerable disability and reduced quality of life associated with the disease [1].
Increased seizure frequency has been identified as a significant negative predictor of health-related quality of life (HRQL), with a higher seizure frequency consistently associated with a poorer quality of life among patients with epilepsy [2]. This relationship is thought to be linked, at least in part, to cerebral hypoxia occurring during seizure episodes; when such events recur, their cumulative effects may precipitate brain dysfunction, including cognitive impairment [3,4]. Cognitive impairment is increasingly recognized as one of the most disabling and frequently overlooked comorbidities of epilepsy, affecting a large proportion of individuals with chronic diseases and representing a major determinant of long-term functional outcomes [5]. Nevertheless, clinical management continues to emphasize seizure control, whereas the cognitive consequences of recurrent seizures are often under-recognized and under-assessed. Therefore, this review synthesizes the current evidence on the relationship between recurrent seizures and cognitive function, encompassing the underlying pathophysiological mechanisms, the cognitive domains most affected, and the screening instruments and biomarkers available for the early detection of cognitive decline in epilepsy.
Epilepsy is a chronic neurological disorder that can occur at any age. The International League Against Epilepsy (ILAE) defines epilepsy as a disease of the brain characterized by any of the following conditions: (1) at least two unprovoked seizures occurring more than 24 h apart; (2) one unprovoked seizure with a probability of further seizures similar to the general recurrence risk (at least 60%) over the next 10 years; or (3) a diagnosis of an epilepsy syndrome, established on the basis of clinical characteristics and electroencephalography (EEG) findings supported by specific etiologies, including structural, genetic, metabolic, immune, and infectious factors [6].
In terms of pathophysiology, epileptic seizures are associated with neuronal hyperexcitability and hypersynchronization of brain activity, which are governed by the balance between excitatory and inhibitory neurotransmitters, namely, glutamate and gamma-aminobutyric acid (GABA). An imbalance between these neurotransmitters, characterized by excessive excitatory activity, leads to increased sodium and calcium ion influx and decreased chloride ion influx. These changes trigger excessive neuronal depolarization, increase the frequency of action potentials, and enhance the propagation of abnormal electrical activity in the brain, ultimately resulting in seizures [7]. Based on this pathophysiology, antiepileptic drugs primarily aim to stabilize neuronal action potentials and electrical activity to prevent seizure occurrence. However, under certain conditions, seizures may still recur, particularly when patients are unable to avoid triggering factors. In addition to non-adherence to antiepileptic drugs (AEDs), several other factors may precipitate recurrent seizures, including smoking, sleep deprivation (less than eight hours), fatigue, and severe emotional stress. Large surveys of people with epilepsy have consistently identified stress, sleep deprivation, and fatigue as the most frequently reported seizure precipitants [8].
The more frequently patients with epilepsy experience seizures, the greater is the negative impact on their quality of life. This is supported by a study conducted by Tran et al., which demonstrated cyclooxygenase-2–dependent vasoconstriction during and after seizure episodes, potentially leading to cerebral hypoperfusion, hypoxia, and even ischemia [9]. When recurrent, this condition may result in cumulative structural and functional damage to the brain tissue. Among all brain regions, lesions are most frequently observed in the hippocampus, a structure that plays a crucial role in memory function, which is one of the key domains of cognition [10,11]. The hippocampus is particularly sensitive to hypoxic and ischemic conditions, rendering it more vulnerable to damage caused by recurrent seizures. Damage to this region can disrupt the processes of memory formation, storage, and retrieval and can also affect other cognitive functions, such as attention and learning ability [12]. Consequently, individuals with epilepsy, particularly those experiencing recurrent seizures, are at an increased risk of cognitive decline.
Cognitive function refers to an individual's ability to recognize objects or situations and is associated with skills, learning experiences, and intellectual capacity. This function encompasses multiple domains, including perception, memory, learning, attention, language, executive function, and orientation [13]. Approximately 60–70% of individuals with chronic epilepsy experience cognitive impairment, which is closely associated with several interrelated factors, including earlier age at epilepsy onset, higher seizure frequency, intensity, and duration of seizures, and the use of antiepileptic drugs [5].
In adults, temporal lobe epilepsy is the most common cause of focal-onset impaired awareness seizures [5]. The temporal lobe plays a crucial role in language (speech), learning, memory, and affective behavior. Temporal lobe epilepsy can affect various domains of cognitive function, including working memory, autobiographical memory, executive function, naming ability, hemispheric lateralization, and language function [14]. Another common form of epilepsy in adults is frontal lobe epilepsy (FLE) [5]. The frontal lobe is essential for higher-order cognitive processes, particularly executive functioning and working memory, and is involved in motor function, emotional regulation, and inhibitory control. Structural and functional disturbances in the frontal lobe, such as focal seizures originating from this region, may lead to cognitive and behavioral impairment. In adults with frontal lobe epilepsy, these impairments commonly manifest as decreased attention and difficulty in performing complex behaviors, particularly those related to executive functions, such as planning, anticipation, organization, initiation, working memory, and task execution [15].
In assessing cognitive function in patients with epilepsy, the use of cognitive screening tools is important for the early identification of impairment. The gold standard for cognitive assessment is comprehensive neuropsychological testing; however, this approach is time-consuming and requires specialized resources. More practical screening instruments, such as the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), can be used as alternatives. The MMSE is the most used tool, particularly for assessing cognitive function related to Alzheimer's disease. However, it has limitations owing to its relatively low sensitivity in detecting mild cognitive impairment and its susceptibility to the influence of age, socioeconomic status, and educational level [16].
In Indonesia, the MoCA was validated in 2010 by Husein et al., resulting in the Indonesian version, the MoCA-Ina [17]. The MoCA was developed as a brief cognitive screening tool to detect mild-to-moderate cognitive impairment and has demonstrated high sensitivity and specificity, particularly for mild cognitive impairment [18]. Furthermore, several studies suggest that the MoCA is more suitable for patients with epilepsy owing to its broader and more comprehensive assessment than the MMSE. One study reported that the MoCA has a sensitivity of 90% and that 87.5% of patients with normal MMSE scores were found to have cognitive impairment when assessed using the MoCA; no patient with a low MMSE score had a normal MoCA result. A strong correlation was observed between the two instruments (r = 0.80), and significant associations were found between memory function and both immediate and delayed recall—and seizure type (p < 0.03) and educational level (p < 0.001) [19]. A study involving 150 subjects (50 patients with temporal lobe epilepsy, 50 patients with other types of epilepsy, and 50 healthy controls) demonstrated a significant difference in mean MoCA scores. Both epilepsy groups had lower scores than the healthy control group (p < 0.05). Cognitive impairment is more severe in temporal lobe epilepsy, particularly in the visuospatial, attention, memory, language, and abstraction domains. Significant risk factors associated with cognitive decline include age, lower educational level, higher seizure frequency, and longer duration of epilepsy [20].
In addition to cognitive screening instruments, cognitive function can also be assessed using biomolecular approaches, one of which is the measurement of brain-derived neurotrophic factor (BDNF) levels. BDNF is an essential protein that plays a critical role in promoting neuronal survival and synaptic plasticity, processes involved in memory and learning [21]. Basic and clinical studies have demonstrated that BDNF exerts broad effects on the nervous system, including neuroprotective roles in various neurological disorders, and is strongly associated with the development of cognitive function. In the context of epilepsy, recurrent seizures are thought to influence the expression and levels of BDNF in the brain, particularly in regions involved in memory function, such as the hippocampus. These alterations in BDNF levels may contribute to the cognitive impairment frequently observed in patients with epilepsy, suggesting that BDNF has potential as a biological marker reflecting the severity of cognitive dysfunction associated with recurrent epileptic activity [22].
Taken together, recurrent seizures contribute to impairments across multiple domains of cognitive function, with varying severity depending on the clinical characteristics and location of the epileptogenic foci. The involvement of brain structures, such as the temporal and frontal lobes, highlights the complex and multidimensional nature of cognitive impairment in patients with epilepsy. This underscores the importance of addressing the cognitive aspects of the management of patients with epilepsy rather than focusing solely on seizure control.
Recurrent seizures significantly contribute to cognitive decline, especially when prolonged and uncontrolled. These impairments are influenced by seizure characteristics and individual factors such as age, educational level, and treatment regimens. Involvement of the temporal and frontal lobes highlights that epilepsy affects multiple cognitive domains. Commonly affected domains include memory, particularly short-term memory and delayed recall, executive functions such as planning, organization, and inhibitory control, attention, concentration, language abilities, especially naming, and visuospatial function. Early detection using cognitive screening instruments, such as the Montreal Cognitive Assessment (MoCA), is essential, and routine cognitive assessment supports comprehensive treatment planning and improves the quality of life of patients with epilepsy.
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The authors would like to thank the Faculty of Medicine, Universitas Trisakti for their support during the preparation of this literature review. The authors also thank all the colleagues who provided valuable input and constructive feedback on the manuscript.