Risk Factors For Recurrence In Epilepsy Patients

INTRODUCTION

Epilepsy is a chronic disorder of the brain characterized by a persistent predisposition to recurrent seizures, accompanied by neurobiological, cognitive, psychological, and social consequences, and it can affect individuals of all ages [1]. According to the World Health Organization, approximately 50 million people worldwide live with epilepsy, approximately 80% of whom reside in low- and middle-income countries, with an estimated 70,000 new cases occurring each year [2]. The rising incidence of epilepsy has been linked to traffic accidents, congenital disabilities, infectious diseases, and the increasing availability and accessibility of health services [2]. In Indonesia, approximately 440,000 of an estimated 1.8 million patients with epilepsy are considered to be at risk of recurrent seizures [3]. Recurrent seizures may be precipitated by a range of risk factors and can, in many patients, be controlled through antiepileptic drug therapy aimed at reducing seizure frequency [4]. Because a substantial proportion of patients continue to experience uncontrolled seizures, a clear understanding of the current evidence regarding the risk factors for recurrence is essential.

With appropriate long-term therapy, an estimated 70%–80% of patients with epilepsy can achieve a quality of life comparable to that of the general population [5]. It is important to recognize that the goal of treatment is not to cure epilepsy per se, but to prevent seizures and their recurrence, which necessitates a sustained, long-term management strategy. Identifying the determinants of recurrence is necessary to support prevention efforts and improve the quality of comprehensive epilepsy care. Accordingly, this narrative review aims to appraise and explain the risk factors for recurrent seizures in patients with epilepsy and provide a clearer picture of the clinical and non-clinical determinants that contribute to seizure recurrence [6].

METHOD

This narrative review was conducted through structured literature searches of the PubMed and Google Scholar databases, supplemented by manual searching of reference lists. The search terms included epilepsy, incidence, prevalence, epidemiology, recurrent seizures, and risk factors for recurrent seizures. Filters were applied to retrieve articles published in English and Indonesian between 2010 and 2026 that involved human subjects and had at least an abstract available. Eligible study designs comprised meta-analyses, systematic reviews, cohort studies, case-control studies, cross-sectional studies, and case reports. Relevant textbooks and clinical practice guidelines were also consulted. The search strategy is summarized in Table 1.

Table 1. Literature search strategy and selection criteria

Parameter	Detail
Databases	PubMed; Google Scholar; manual searching of reference lists
Search terms	Epilepsy, Incidence, Prevalence, Epidemiology, Recurrent Seizures, Risk Factors For Recurrent Seizures
Language	English and Indonesian
Publication period	2010–2026
Subjects	Human studies; abstract available at minimum
Eligible designs	Meta-analyses; systematic reviews; cohort; case–control; cross-sectional studies; case reports
Additional sources	Reference textbooks and clinical practice guidelines

Definition, Classification, and Epidemiology of Epilepsy

Epilepsy is clinically defined by abnormal neuronal activity in the brain, resulting in transient clinical signs or symptoms, and is a chronic and heterogeneous neurological disorder [7]. Based on etiology, epilepsy is traditionally classified as either idiopathic (primary) or symptomatic (secondary). Primary epilepsy has no identifiable cause and may have a genetic basis, whereas secondary epilepsy has an identifiable cause, such as a brain tumor, stroke, or severe head injury [1]. Globally, of the approximately 50 million people living with epilepsy, the majority reside in low- and middle-income countries; it is estimated that more than 75% of patients in low-income settings and approximately 60% in middle-income settings do not receive appropriate treatment [7]. These figures highlight the disproportionate burden of epilepsy and the greater vulnerability associated with limited economic resources.

Mechanisms of Epileptogenesis and Seizure Recurrence

Epileptogenesis is the process by which neural networks capable of generating spontaneous seizures are formed, leading to the development or progression of epilepsy [8]. This process is closely associated with neuronal injury, gliosis, and microglial activation, which together create a neuroinflammatory environment in the brain, whether arising from intrinsic disorders of the central nervous system or from disruption of the blood–brain barrier [9]. The development of epilepsy is characterized by structural and molecular changes that increase neuronal hyperexcitability and the propensity for recurrent seizures. Following seizures, microglial activation drives the release of proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), which modulate synaptic plasticity, neurotransmission, and neuronal excitability through effects on glutamate receptors and the GABAergic system [10].

An imbalance between excitation and inhibition is the central mechanism underlying both epileptogenesis and ictogenesis. Increased extracellular glutamate levels and/or reduced GABAergic activity can lead to excitotoxicity, seizures, and neuronal death. Glutamate homeostasis depends on the coordinated function of neurons and astrocytes through transporter systems and the glutamate–glutamine cycle; disruption of these mechanisms contributes to neuronal hyperexcitability [11]. Dysregulation of the glutamatergic system, whether due to neuron–astrocyte dysfunction or genetic factors such as N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor mutations, can result in excessive glutamate receptor activation [12]. This promotes excitotoxicity and neural tissue remodelling, which underlie the development of epilepsy and the occurrence of recurrent seizures [13]. The sequence of events linking an initial insult to recurrent seizures is depicted in Figure 1.

Figure 1. Conceptual pathway of epileptogenesis leading to recurrent seizures. An initial precipitating insult triggers neuroinflammation and excitation–inhibition imbalance, driving structural and molecular remodelling, neuronal hyperexcitability, and a lowered seizure threshold; seizures, in turn, reinforce inflammation through a positive feedback loop. BBB, blood–brain barrier; GABA, γ-aminobutyric acid; IL, interleukin; TNF-α, tumor necrosis factor-α.

Risk Factors For Seizure Recurrence

Epilepsy is characterized by recurrent seizures occurring more than 24 h apart, which may arise without an identifiable provocation. Recurrent seizures are a clinical manifestation of excessive and abnormal cortical electrical activity and may give rise to a range of disturbances. Several factors are known to precipitate or increase seizure frequency in patients with epilepsy; these are commonly referred to as triggers. Recognizing such triggers may help patients avoid them and thereby reduce recurrence. The principal determinants identified in this review are summarized in Figure 2 and can be grouped into etiological factors, modifiable behavioral and lifestyle factors, and neuroimaging markers.

Aetiological Factors

In 2019, the Indonesian Neurological Society (PERDOSSI) categorized the etiology of epilepsy into six groups: structural, genetic, infectious, metabolic, immunological, and unknown (idiopathic) [1]. Structural causes include anatomical abnormalities, such as stroke, head injury, infection, or malformation of the cerebral cortex, which may increase the risk of recurrent seizures by 50%–70% due to permanent lesions that disrupt neuronal inhibitory mechanisms. Genetic factors involve gene mutations, in which seizures are the principal manifestation, as in childhood absence epilepsy and juvenile myoclonic epilepsy, which tend to be refractory. Infectious etiologies include epilepsy related to intracranial or post-infectious processes, such as neurocysticercosis, tuberculosis, human immunodeficiency virus (HIV) infection, and congenital infections. Metabolic causes are associated with specific metabolic disorders that require targeted management, whereas immunological etiologies arise from autoimmune processes that induce central nervous system inflammation. In the unknown (idiopathic) category, the cause cannot be definitively established, and the diagnosis relies on clinical characteristics and electroencephalography (EEG) findings [7]. These categories are summarized in Table 2.

Table 2. Etiological classification of epilepsy and its relevance to seizure recurrence

Category	Representative causes / examples	Relevance to recurrence
Structural	Stroke, head injury, infection, cortical malformation	Permanent lesions disrupt neuronal inhibition; recurrence risk increased by 50–70%
Genetic	Gene mutations (e.g., childhood absence epilepsy, juvenile myoclonic epilepsy)	Tendency toward refractory seizures
Infectious	Neurocysticercosis, tuberculosis, HIV, congenital infections	Intracranial or post-infectious epileptogenesis
Metabolic	Specific metabolic disorders	Require targeted, cause-specific management
Immunological	Autoimmune central nervous system inflammation	Inflammation-driven hyperexcitability
Unknown (idiopathic)	No identifiable cause	Diagnosis based on clinical features and EEG findings

Note: Classification according to the Indonesian Neurological Society (PERDOSSI, 2019). EEG, electroencephalography; HIV, human immunodeficiency virus.

Modifiable Behavioural and Lifestyle Factors

Antiseizure Medication Non-Adherence

Adherence to antiseizure medication is a key determinant of seizure recurrence. Non-adherence has been reported to contribute to 29% of recurrent seizures [14]. In a cross-sectional study, forgetting to take antiseizure medication was associated with focal-to-bilateral tonic–clonic seizures, reflecting the fact that antiseizure drugs stabilize neuronal activity within the epileptogenic focus [15]. When doses are missed, plasma drug concentration decreases and the stabilizing effect on the epileptogenic focus is diminished, thereby increasing the likelihood of seizures.

Sleep Deprivation

Approximately 40%–50% of patients with epilepsy report that fatigue, lack of sleep, and skipping meals can trigger more frequent seizures [16]. An observational study of 44 patients found that poor sleep quality increased the risk of more than one seizure approximately tenfold (p = 0.003) [17]. Sleep deprivation generally lowers the seizure threshold by disrupting brain electrical activity during non-rapid eye movement (NREM) sleep. Irregular eating patterns, such as habitually skipping meals, may also act as a trigger, as inconsistent food intake can precipitate hypoglycemia, dehydration, and metabolic imbalance, which increase neuronal excitability and lower the seizure threshold [18]. These observations indicate that nutritional factors influence not only general health status but also seizure control, making regular meal patterns an important component of comprehensive epilepsy management.

Psychological Stress

Severe stress is thought to trigger seizures in some patients through both psychological and physiological mechanisms, and it is the most commonly reported seizure trigger. In one study, 86.9% of patients reported awareness of the early symptoms and triggers of their seizures [19]. Consistent with this, higher stress levels have been associated with greater seizure frequency [20]. The physiological stress response is mediated by the neuroendocrine system and involves multiple brain regions, including the amygdala, cingulate and prefrontal cortex, septohippocampal region, hypothalamus, and brainstem structures. Two principal components—the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic–adrenomedullary (SAM) system—contribute to seizure generation [21].

Alcohol Consumption

Alcohol consumption is a known trigger of seizures in patients with epilepsy. Acutely, alcohol can suppress central nervous system excitability and reduce epileptiform activity on EEG by enhancing GABAergic inhibition. However, as the blood alcohol concentration decreases, epileptiform activity on EEG increases, and this withdrawal phase is associated with a higher risk of seizures [22].

Smoking

Smoking may be associated with an increased risk of seizures, particularly among individuals with greater smoking frequency and duration. Nicotine, the principal addictive component of cigarettes, exerts proconvulsant effects by activating nicotinic acetylcholine receptors (nAChRs) in the brain; individuals with slower receptor desensitization may exhibit greater seizure susceptibility after nicotine exposure [23]. Smoking appears to be relatively common among individuals with epilepsy. A cross-sectional study reported a smoking prevalence of 32.1% among patients with epilepsy, which is higher than the corresponding general population estimate of 19.0% in Switzerland, although another study in Western China found a lower prevalence among men with epilepsy than that in the general population [24]. The relationship between smoking and epilepsy remains complex and partly controversial, as several prospective studies have linked smoking to an increased risk of seizures—including isolated or provoked seizures unrelated to stroke—and to a higher likelihood of refractory epilepsy.

Nutritional Factors

As noted above, irregular dietary patterns can contribute to seizure recurrence. Skipping meals and inadequate nutritional intake may lead to hypoglycemia, dehydration, and metabolic disturbance, each of which can heighten neuronal excitability and lower the seizure threshold [18]. Therefore, attention to consistent nutrition is a part of comprehensive seizure management.

Table 3. Modifiable behavioral, lifestyle, and imaging-related risk factors for seizure recurrence

Risk factor	Proposed mechanism	Key evidence	Ref.
Medication non-adherence	Reduced plasma drug levels destabilise the epileptogenic focus	Contributed to 29% of recurrences; missed doses linked to focal-to-bilateral tonic–clonic seizures	14, 15
Sleep deprivation	Lowered seizure threshold via disrupted NREM electrical activity	Poor sleep quality increased risk ~10-fold (n = 44; p = 0.003); 40–50% report sleep/fatigue triggers	16, 17
Psychological stress	HPA-axis and SAM-system activation; limbic involvement	Most commonly reported trigger; 86.9% aware of triggers; higher stress → higher frequency	19–21
Alcohol consumption	Acute GABAergic suppression with rebound epileptiform activity on withdrawal	Increased epileptiform EEG activity during the withdrawal phase	22
Smoking (nicotine)	nAChR activation with proconvulsant effects	Prevalence 32.1% vs 19.0% in the general population; associated with increased seizure risk	23, 24
Irregular meals / nutrition	Hypoglycaemia, dehydration, and metabolic imbalance	Inconsistent intake increases excitability and lowers seizure threshold	18
Abnormal MRI findings	Structural epileptogenic foci (e.g., hippocampal sclerosis, cortical lesions)	59.5% of patients (47/79) had abnormal MRI findings	25, 26

EEG, electroencephalography; GABA, γ-aminobutyric acid; HPA, hypothalamic–pituitary–adrenal; MRI, magnetic resonance imaging; nAChR, nicotinic acetylcholine receptor; NREM, non-rapid eye movement; SAM, sympathetic–adrenomedullary.

Neuroimaging Findings

Abnormal neuroimaging is an important marker of recurrence risk in patients with glioblastoma. In a hospital-based study, 47 of 79 patients (59.5%) had abnormal MRI findings, consistent with epidemiological evidence that structural brain abnormalities are the most frequent cause of focal seizures [25]. Structural abnormalities detected on MRI, such as hippocampal sclerosis and cortical lesions, can act as epileptogenic foci that precipitate seizures in patients with epilepsy [26].

Figure 2. Conceptual framework of risk factors for seizure recurrence in patients with epilepsy. Etiological factors, modifiable behavioral and lifestyle factors, and an abnormal neuroimaging marker converge on a shared pathophysiology of neuronal hyperexcitability, lowered seizure threshold, and neuroinflammation, ultimately resulting in recurrent seizures. HPA, hypothalamic–pituitary–adrenal; MRI, magnetic resonance imaging; nAChR, nicotinic acetylcholine receptor; SAM, sympathetic–adrenomedullary.

DISCUSSION

The evidence synthesized in this review indicates that seizure recurrence in epilepsy is not attributable to any single determinant but rather emerges from the interaction of etiological, mechanistic, and behavioral factors. Etiological categories—particularly structural causes such as stroke, head injury, intracranial infection, and cortical malformation—establish a durable substrate for recurrence through permanent lesions that impair neuronal inhibition, whereas genetic syndromes contribute to a tendency toward refractoriness [17]. At the pathophysiological level, epileptogenesis is characterized by microglial activation, proinflammatory cytokine release, and an excitation–inhibition imbalance that together heighten neuronal hyperexcitability and facilitate recurrence [10,11]. These mechanistic processes provide a unifying framework that links non-modifiable etiologies and modifiable triggers to a common downstream pathway, as illustrated in Figures 1 and 2.

Crucially, several of the most influential determinants are modifiable. Non-adherence to antiseizure medication, sleep deprivation, psychological stress, alcohol consumption, smoking, and irregular nutrition each lower the seizure threshold and are, in principle, amenable to intervention [21]. Abnormal MRI findings serve as clinically accessible markers that can help identify patients at an elevated risk of recurrence [25]. Taken together, these observations support a comprehensive, individualized approach to epilepsy care that combines adherence support, lifestyle counselling, and structured neuroimaging assessment. Limitations. This work is a narrative rather than a systematic review; accordingly, it did not employ a formal study-selection protocol, risk-of-bias appraisal, or quantitative synthesis, and selection bias cannot be excluded. The included studies were heterogeneous in terms of design, setting, and population, and several reported associations were derived from small samples or single-center cohorts, which limits generalizability. The relationship between certain factors—most notably smoking—and seizure recurrence remains incompletely resolved. These limitations should be considered when interpreting the findings, and future prospective, adequately powered studies are warranted to quantify the independent contribution of each risk factor.

CONCLUSION

Recurrent seizures in epilepsy result from interactions among etiological factors, epileptogenesis, and behavioral factors. Structural causes, such as stroke, head injury, intracranial infection, and cortical malformation, increase the risk of recurrence through lesions that disrupt neuronal inhibition, whereas genetic factors contribute to refractory syndromes. Microglial activation, proinflammatory cytokine release, and excitation–inhibition imbalance increase neuronal hyperexcitability. Modifiable triggers, including medication non-adherence, sleep deprivation, stress, alcohol use, and smoking, lower the seizure threshold and indicate risk. Controlling risk is essential for preventing recurrence and improving quality of life.

DECLARATIONS

None

CONSENT FOR PUBLICATION

The authors agree to the publication of this article in the Journal of Society Medicine.

FUNDING

This research did not receive any specific grants from any funding agency in the public, commercial, or not-for-profit sectors.

COMPETING INTERESTS

All authors have reviewed and approved the final version of the manuscript and have agreed to its publication in the Journal of Society Medicine.

AUTHORS’ CONTRIBUTIONS

All authors have reviewed and approved the final version of the manuscript, and they all agree to be accountable for all aspects of the work.

ACKNOWLEDGMENTS

The authors thank the Faculty of Medicine, Universitas Trisakti, for their institutional support. No external funding was received for this work, and no person other than the listed authors contributed substantively to the manuscript.

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