Geriatric epilepsy, characterized by an onset at or beyond the age of 65 years (Cloyd et al., 2006), presents a distinct epidemiological pattern. Epidemiological studies have delineated a bimodal distribution of epilepsy incidence, observing heightened rates in both young children and the elderly. Notably, the incidence of epilepsy escalates progressively post-50 years of age, reaching its zenith in individuals aged 75 and above (Hauser et al., 1993; Collaborators, 2019). In elderly patients, seizures are typically localized to specific brain regions, with convulsive symptoms being comparatively infrequent (Godfrey, 1989). This often leads to misdiagnoses of seizures as fainting or transient loss of consciousness in older adults (Ramsay et al., 2004). Such patients are at an increased risk of cognitive decline and psychiatric complications, factors that augment the likelihood of status epilepticus and related mortality (DeLorenzo et al., 1996; Martin et al., 2005).

Furthermore, geriatric populations exhibit heightened sensitivity to antiepileptic drugs, necessitating lower initial dosages and a more meticulous approach to medication regimen (Werhahn et al., 2011). Cerebrovascular disease is identified as the predominant cause of epilepsy in the elderly (Hauser et al., 1993), while blood–brain barrier (BBB) dysfunction emerges as a common pathological feature in this cohort (van Vliet and Marchi, 2022). Alterations in BBB functionality significantly influence drug delivery to the brain (Movahedpour et al., 2023), underscoring the need for a nuanced understanding of BBB dynamics in the context of elderly epilepsy treatment.

This review aims to elucidate the structure and function of the BBB and its role in the pathogenesis of geriatric epilepsy. It will also examine the impact of BBB on pharmacotherapy in elderly epileptic patients. Finally, the paper will explore innovative approaches to antiepileptic therapy, particularly strategies aimed at mitigating or circumventing BBB challenges, thereby offering fresh perspectives and strategies for treating geriatric epilepsy.

Comprehensive understanding of the BBB’s structure and the regulatory mechanisms of its permeability is paramount for developing diagnostic tools to assess BBB integrity and therapeutic interventions aimed at preserving or restoring normal BBB function in CNS diseases. The BBB is a critical selective barrier (Figure 1), constituted by brain endothelial cells, which regulates molecular exchanges between the bloodstream and neural tissue (Abbott et al., 2006). Its functionality hinges on the integrity of the neurovascular unit, comprising endothelial cells, pericytes, astrocytes, neurons, and the basement membrane (Sá-Pereira et al., 2012; Sweeney et al., 2016; Wang et al., 2021). Structurally, the BBB primarily consists of brain microvascular endothelial cells (BMECs) interconnected by tight junctions, adherens junctions, and gap junctions (Beard Jr et al., 2011; Spéder and Brand, 2014; Li et al., 2015). These intercellular junctional complexes significantly restrict the paracellular diffusion of solutes (Petty and Lo, 2002). Moreover, brain pericytes, astrocytic end-feet, neurons, and the extracellular matrix coalesce to form the neurovascular unit alongside BMECs, playing a pivotal role in inducing BBB properties during development and maintaining its integrity in adulthood (Kadry et al., 2020).

According to Yu et al. (2015), BMECs are distinguished from peripheral endothelial cells by their markedly low pinocytic activity and absence of fenestrations. The transcellular pathway across the BBB is intricately regulated by an array of membrane transporters and metabolic enzymes expressed in BMECs (Pottiez et al., 2009). Key efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein actively expel xenobiotics back into the bloodstream, whereas solute carrier transporters facilitate the influx of nutrients and ions into the brain (Kodaira et al., 2011). Additional membrane proteins and enzymes play crucial roles in controlling transcellular permeability (Raleigh et al., 2010; Del Vecchio et al., 2012; Sweeney et al., 2016). BMECs, in conjunction with the neurovascular unit, dynamically regulate BBB permeability to balance the metabolic demands of the central nervous system and protect against blood-borne toxins and pathogens (Daneman and Prat, 2015; Yan et al., 2021).

In various central nervous system disorders, including stroke (Bernardo-Castro et al., 2020), seizures (Uzüm et al., 2006), multiple sclerosis (Cramer et al., 2014), Alzheimer’s disease (Rosenberg, 2014), and brain tumors (Gerstner and Fine, 2007), BBB disruption is implicated, leading to increased permeability. This disruption facilitates the influx of potentially neurotoxic plasma components into the brain parenchyma (Keaney and Campbell, 2015). Diseases common in the elderly population, such as aging, hypertension, and diabetes, can further impair the integrity and functionality of the BBB (Zlokovic, 2008; Popescu et al., 2009; Prasad et al., 2014; Katsi et al., 2020).

Neuroimaging studies of the living human brain have revealed that disruptions in the BBB within the hippocampus are strongly linked to aging, a correlation that is particularly pronounced in patients with mild cognitive impairment (van de Haar et al., 2016; Sweeney et al., 2018; Nation et al., 2019). This phenomenon is corroborated by animal model studies, which have shown that the downregulation of tight junction proteins such as claudin-5 and occludin occurs with age, resulting in increased paracellular permeability of the BBB (Keaney and Campbell, 2015; Bors et al., 2018; Knox et al., 2022).

As part of the aging process, the BBB undergoes considerable structural and functional degradation (Figure 1). This degradation becomes evident when the BBB is compromised, manifesting in extensive alterations in comparison to a healthy state (Persidsky, 1999; Knox et al., 2022). Notable age-related changes in the BBB include significant modifications in cell-to-cell interactions, resulting in endothelial cell degeneration or atrophy and the reduced expression or mislocalization of tight junction proteins (Obermeier et al., 2013; Sweeney et al., 2019b). These alterations critically affect paracellular transport mechanisms (Erdő et al., 2017). Pathological conditions further lead to the upregulation of leukocyte adhesion molecules in endothelial cells, promoting leukocyte infiltration into the brain parenchyma and exacerbating oxidative stress through the release of reactive oxygen species, cytokines, and other mediators (Brochard et al., 2009; Gerwien et al., 2016; Profaci et al., 2020; Iannucci and Grammas, 2023; Figure 2). The heightened Reactive oxygen species consumption within the brain amplifies its vulnerability to oxidative stress (Segarra et al., 2021), with deleterious effects including oxidative damage to cellular components, activation of matrix metalloproteinases, and dysregulation of tight junction proteins and inflammatory mediators (Pun et al., 2009; Olmez and Ozyurt, 2012; Obermeier et al., 2013). These disruptions impair key cellular functions, including transport, energy production, and ion homeostasis (Olmez and Ozyurt, 2012). Additionally, the efficiency of P-gp in the BBB diminishes from middle age onwards, exacerbating the BBB’s transport dysfunction in conjunction with neuropathological burdens (Chiu et al., 2015; Banks et al., 2021).

At the cellular level, the process of aging is correlated with a notable reduction in the density and coverage of BMECs and pericytes. This reduction is particularly pronounced in brain regions that are more susceptible to age-related degeneration, such as the hippocampus (Montagne et al., 2015; Verheggen et al., 2020). Importantly, this decline associated with aging encompasses not just cellular density but also includes significant changes in the heterogeneity of astrocytes, oligodendrocytes, and microglia. These alterations collectively exert a profound impact on brain clearance mechanisms, myelination processes, and immune surveillance within the central nervous system (Kettenmann et al., 2011; Rodríguez-Arellano et al., 2016). Furthermore, changes in pericyte behavior, alongside alterations in glial cell function, are known to adversely affect BBB permeability and are implicated in the exacerbation of brain inflammation, further complicating the pathophysiological landscape (Rustenhoven et al., 2017; Sweeney et al., 2019a).

Consequently, this decline in BBB integrity and functionality has profound implications for neuronal health. BBB damage can precipitate epileptic seizures through various interconnected mechanisms. The compromised barrier allows for the leakage of substances such as potassium, albumin, or immune cells, which are intrinsically associated with abnormal neuronal firing (Seiffert et al., 2004; David et al., 2009; Fabene et al., 2010). Furthermore, BBB deterioration alters the balance of adenosine and glutamate transporters and catalytic enzymes, characterized by a decrease in adenosine and a elevation in glutamate levels, contributing to an increase in neuronal excitability (Grant et al., 2003; Parkinson et al., 2003). Additionally, BBB disruption can lead to a decrease in pH, negatively impacting the coupling of cerebral blood flow to neuronal activity and resulting in enhanced neuronal firing (Aaslid, 2006). These changes disrupt the central nervous system’s ‘excitation-inhibition’ balance, potentially initiating or intensifying epileptic symptoms.

Among the various pathways implicated in this disruption, the role of transforming growth factor beta (TGFβ)-associated pathway stands out as particularly significant in the progression of epilepsy, especially among the elderly (Figure 2). Research utilizing rodent models to emulate BBB leakage has elucidated that the infusion of serum albumin precipitates the activation of TGFβ signaling within astrocytes. This activation is implicated in engendering age-related neurological dysfunctions, brain aging phenotypes, heightened susceptibility to epilepsy, and cognitive impairments, as evidenced by several studies (Cacheaux et al., 2009; Milikovsky et al., 2019; Senatorov Jr et al., 2019). Itai et al. have highlighted the crucial role of the astrocyte ALK5/TGF-β pathway in mediating excitatory synaptogenesis post-BBB disruption, leading to seizures (Weissberg et al., 2015). Furthermore, the presence of albumin in the brain mediates the downregulation of potassium channels in astrocytes through TGFβ receptors, impacting potassium buffering and leading to increased extracellular potassium levels and neuronal overexcitability, thereby inducing epileptic discharges. The blockade of TGFβ receptors has been shown to significantly reduce the incidence of albumin-induced epilepsy (Ivens et al., 2007). Subsequent research revealed that serum-derived albumin preferentially activates the TGF-β receptor I activin receptor-like kinase 5 pathways in astrocytes. Notably, the TGF-β signaling inhibitor losartan effectively inhibits this pathway, preventing delayed recurrent spontaneous seizures, with effects lasting for weeks after drug discontinuation, highlighting its therapeutic potential (Bar-Klein et al., 2014).

In the management of epilepsy among elderly patients, antiepileptic drugs (AEDs) play a crucial role (Vu et al., 2018). Compared to their younger counterparts, older adults may derive greater benefits from AEDs but are simultaneously at an elevated risk for potential side effects (Hernández-Ronquillo et al., 2018). Consequently, in geriatric epilepsy treatment, the initial dosing and dosage increments of AEDs are typically reduced to half of those prescribed for younger individuals to enhance drug tolerance. It is often observed that elderly patients require only half the standard dose recommended for patients under 65 years of age (Sen et al., 2020). Moreover, the selection of appropriate AEDs for older adults is constrained by the increased likelihood of side effects and drug–drug interactions. For instance, traditional AEDs such as carbamazepine and phenytoin are often eschewed due to their adverse impacts on bone health, lipid metabolism, balance, and their propensity for enzyme induction (Sen et al., 2020). A meta-analysis has indicated that lamotrigine is better tolerated than carbamazepine in the elderly with epilepsy. Additionally, levetiracetam demonstrated a higher probability of seizure control compared to lamotrigine, with no significant difference in tolerability. Furthermore, no notable differences in efficacy and tolerability were observed between carbamazepine and levetiracetam (Lezaic et al., 2019). Another meta-analysis posited that lacosamide, lamotrigine, and levetiracetam are the most effective in terms of achieving seizure remission for old patients (Lattanzi et al., 2019). Patients with drug-resistant epilepsy, particularly older adults, may require an increased number of medications to control seizures and are more vulnerable to the neurotoxic effects of specific drugs (Trinka, 2003). This situation highlights the ongoing need for research into various drug delivery methods, including those involving the BBB.

The BBB defined by its intricate tight junctions and sophisticated efflux transport systems, is a critical physiological structure. Its role extends beyond the mere obstruction of drug delivery to the brain; it also regulates the distribution of therapeutic agents within brain tissues, presenting a significant challenge in treating central nervous system disorders (Cardoso et al., 2010; Li et al., 2011). Contemporary research has identified three protective mechanisms that drugs targeting the central nervous system encounter when interacting with the BBB (Angelow and Yu, 2007; Pardridge, 2007). The first is the enzymatic barrier, which restricts the entry of drugs and organic substances into capillary endothelial cells. The second is the cellular barrier, composed of contacts between BBB cells, where endothelial cells limit the passage of water-soluble substances and regulate vesicular transport and endocytosis. The third mechanism involves the ATP-binding cassette protein transport system, actively extruding certain drugs from the endothelial cells of brain blood vessels.

The BBB’s significance is particularly notable in epilepsy treatment, as it impedes the penetration of biotechnological drugs into the brain, thereby diminishing the effectiveness of antiepileptic medications (Zhao et al., 2020). In elderly epilepsy patients, a disrupted BBB structural integrity has been observed, which introduces complexities in traditional antiepileptic drug therapies. While it might seem intuitive that a compromised BBB would allow greater drug access to the brain, the reality is more nuanced. In fact, BBB leakage enables the entry of serum albumin into the brain, which adversely affects the brain distribution of many antiepileptic drugs that bind to plasma proteins, leading to suboptimal treatment outcomes (Marchi et al., 2009; Salar et al., 2014). Moreover, damage to the BBB can result in an increased expression of various drug transporters. This phenomenon contributes to pharmacoresistance in epilepsy, particularly due to the overexpression of ATP-binding cassette efflux transporters like P-gp and breast cancer resistance protein (van Vliet et al., 2014; Gonçalves et al., 2021). The excessive presence of these transporters restricts the entry of antiepileptic drugs into the brain, thereby playing a crucial role in the development of resistance to these drugs. Furthermore, oxidative stress, whether due to disease progression or AED side effects, may alter the expression of these BBB transport proteins (Grewal et al., 2017). Additionally, genetic variations and the increased expression of efflux transporter genes could be potential factors in pharmacoresistance. These transporters collaboratively act to inhibit antiepileptic drugs from delivering their therapeutic impact on the central nervous system (Soares et al., 2016).

Traditionally, one potential strategy to counteract the reduction in drug concentration within the central nervous system, caused by BBB disruption in elderly epilepsy patients, has been to increase the drug dosage. However, it is important to acknowledge that while most antiepileptic drugs can penetrate brain tissue, they also distribute to other organs, potentially leading to significant systemic toxicity (Perucca, 2002; Li and Ma, 2006). Such chronic toxicity, encompassing hematological disorders, hepatotoxicity, and other adverse effects, considerably constrains the clinical application of antiepileptic drugs (Perucca and Gilliam, 2012; Schmidt and Schachter, 2014). Consequently, developing targeted drug delivery systems specifically designed for the central nervous system may offer a promising approach to enhance drug efficacy in the brain while minimizing peripheral side effects. This strategy could prove invaluable in optimizing therapeutic outcomes in the treatment of epilepsy, particularly in the elderly.

Contemporary approaches to drug administration across the BBB have been extensively reviewed in prior literature (van Vliet and Marchi, 2022), and thus, will not be reiterated here. In summary, the current therapeutic strategies for managing epilepsy in elderly patients predominantly encompass four mechanistic pathways: the modulation of pro- and anti-inflammatory balance (Fabene et al., 2008), the PDGF/TGF signaling pathways (Shen et al., 2019), pathways addressing oxidative stress (Luo et al., 2018), and the manipulation of matrix metalloproteinases (Broekaart et al., 2021). While these methodologies have shown potential in restoring cerebral vascular integrity and broadly controlling brain inflammation, their efficacy in epilepsy management and the efficiency of drug delivery via these mechanisms warrant further investigation. Given the unique physiological attributes of the BBB, there is a critical need for research focused on enhancing drug delivery efficiency through the BBB. Alternatively, exploring methods to directly bypass the BBB for the targeted delivery of antiepileptic drugs to the central nervous system is equally imperative. Here, we explore recent advancements in strategies designed to bypass the BBB for effective drug delivery to the central nervous system (Figure 3).

In summary, this review underscores the paramount importance of comprehending the dynamics of the BBB in managing epilepsy in the elderly. Although various innovative anti-epileptic strategies targeting the BBB have been discussed, their efficacy in elderly patients with epilepsy necessitates further exploration. With the rising prevalence of epilepsy in an aging population, unique pharmacological challenges emerge due to age-related alterations in the BBB. Future research endeavors should be directed towards understanding how these novel treatment strategies can be optimized in the context of such age-associated pathological changes. Given the intricacy of the BBB, advancements in targeted therapy and non-invasive drug delivery methods hold promise for enhancing treatment efficacy and, consequently, the quality of life for the elderly. The integration of precision medicine and emerging technologies in this field aims not only to ameliorate health outcomes but also to enrich our understanding of the aging nervous system. Adopting this approach will facilitate more personalized and compassionate care for our aging society, ultimately contributing to improved health management and enhanced quality of life for individuals with geriatric epilepsy.

XC: Writing – original draft, Writing – review & editing. JL: Writing – review & editing, Investigation. MS: Writing – review & editing. LP: Writing – review & editing. ZQ: Data curation, Software, Writing – review & editing. BH: Conceptualization, Software, Writing – review & editing. SY: Writing – review & editing. HS: Writing – review & editing.