Seizure after stroke or post-stroke seizure is a common and very important complication of stroke. Ischemic and hemorrhagic strokes together account for a large portion of adult epilepsy cases, particularly in older adults. More and more researchers have devoted themselves to the study of post-stroke seizures and post-stroke epilepsy. A comprehensive understanding of the pathogenesis of post-stroke seizure is of great significance for the treatment and prevention of the disease.

As a leading provider of stroke research services, Ace Therapeutics is committed to helping clients explore the molecular mechanisms, biomarkers, and treatment targets of seizures and epilepsy after stroke in different circumstances.

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• Pathogenic Mechanism Analysis Services for Stroke
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What Is a Seizure?

Seizure is the most common neurological disorder and a chronic brain disease with multiple causes. It is characterized by excessive discharges of certain neurons in the nervous system. This electrical disturbance may occur as a result of damage to the brain from a stroke.

Post-stroke Seizure and Post-stroke Epilepsy

The terms "post-stroke seizure" and "post-stroke epilepsy" are often used interchangeably in studies involving seizures after stroke, but they represent distinct clinical conditions based on their definitions and underlying pathology. Traditionally, epilepsy is defined as having two or more unprovoked seizures occurring more than 24 hours apart. Currently, some research has opted to define post-stroke epilepsy strictly as the occurrence of two unprovoked seizures after a stroke.

Fig. 1 An illustration of epileptogenesis following stroke. (Tanaka, et al., 2024)

Classification of Post-Stroke Seizure

There are various seizure types after stroke, and the occurrence of epilepsy is closely related to the type and location of stroke. Post-stroke seizures can be classified into early-onset and late-onset categories, as their underlying pathological mechanisms and the associated risk of progressing to epilepsy differ significantly.

• Early-onset epileptic seizures occur within the first week after a stroke, primarily within 24h. Early epileptic seizures do not form a stable epileptic network, and the brain has the ability to self-repair. Therefore, patients are diagnosed with seizures rather than epilepsy.
• Late-onset epilepsy arises more than a week after a stroke, peaking between 6 to 12 months later, and is characterized by stable epileptogenic foci and a higher likelihood of recurrent seizures, leading to a diagnosis of epilepsy.

Fig. 2 Early and late seizures: Shifting from a time-based to a tissue-based approach. (Tanaka, et al., 2024)

The Pathogenic Mechanisms of Early-onset Epileptic Seizures

Elevated Serum Cortisol Levels

In the early stages of ischemic stroke, the activation of the hypothalamic–pituitary–adrenal (HPA) axis leads to a significant increase in serum cortisol levels. Cortisol is neurotoxic and exacerbates hypoxic damage to neurons and astrocytes, disrupts glucose metabolism in the brain, and promotes epileptic seizures. Additionally, high cortisol levels can enhance neuronal excitability by influencing glutamate receptors on the postsynaptic membrane. Further research shows that elevated cortisol reduces the number of neurons in the hippocampal CA3 region and disrupts neurogenesis in adult rats, leading to structural and functional changes in the temporal lobe, which contribute to recurrent seizures.

Neurotransmitter Imbalance

Early-onset epileptic seizures can be triggered by an imbalance in neurotransmitters, particularly the excitatory glutamate and inhibitory γ-aminobutyric acid (GABA). Under normal conditions, these neurotransmitters maintain a dynamic balance that stabilizes neural networks. After a stroke, ischemia and hypoxia lead to excessive release of glutamate, overstimulating glutamate receptors, and increasing neuronal excitability, which makes the brain more prone to seizures. Additionally, stroke reduces the levels of GABA receptors, specifically the α1 subunit, and impairs their transport to the cell membrane, weakening inhibitory signals and lowering the seizure threshold. Furthermore, early ischemic stroke reduces GABA levels and activity, leading to enhanced NMDAR-mediated nitric oxide (NO) production, which increases neuronal excitability by blocking M-type K⁺ channels, further facilitating seizures.

Ion Channel Dysfunction

Stroke-induced acute ischemia and hypoxia disrupt neuron membrane stability and metabolism, leading to sodium pump failure, increased Na⁺ influx, and membrane depolarization. As the depolarization reaches a threshold, calcium channels are activated, allowing Ca²⁺ influx and raising intracellular Ca²⁺ levels. This causes neuronal overexcitation, excitotoxicity, and a loss of function in local suppressor cells. When these suppressor cells can no longer control the spread of hypersynchronous discharges, epilepsy can develop.

Deposition of hemosiderin

In hemorrhagic stroke, 4–16% of patients experience epileptic seizures following intracerebral hemorrhage. Hemosiderin deposition, particularly after subarachnoid hemorrhage, is linked to early seizures. The iron released from hemosiderin induces oxidative stress by generating hydroxyl radicals, which affect cortical neurons and promote epilepsy. Free radicals and free iron also cause structural changes around the hemorrhage site, leading to synaptic reorganization and seizure induction.

Other Mechanisms

Additional mechanisms contributing to early seizures include acute electrolyte imbalances (increased calcium and sodium concentrations) in the ischemic penumbra, depolarization of neuronal membranes, elevated extracellular glutamate, and impaired function of GABAergic interneurons. These changes lead to diffuse depolarization, which can spread from the ischemic penumbra to the ischemic core, triggering seizures. Ischemia-reperfusion injury from recanalization during acute ischemic stroke, or ischemia from vasospasm in hemorrhagic stroke, also increases neuronal excitability, raising the risk of seizures.

The Pathogenic Mechanisms of Late-onset Epilepsy

Blood-Brain Barrier (BBB) Damage

During ischemic stroke, the BBB is compromised, allowing blood components, including albumin, to leak into brain tissue and impair neuronal function. This BBB damage can lead to vasogenic brain edema and increased neuronal excitability, contributing to late-onset epilepsy. Extravasated albumin binds to the TGFβ receptor on astrocytes, activating TGFβ signaling and reducing the function of inward rectifier potassium (KIR4.1) and water (AQP4) channels. This impairs the astrocytes' ability to clear K+ and glutamate, increasing extracellular concentrations of these ions and promoting excitotoxicity, which can trigger seizures.

Additionally, after stroke, inflammatory mediators like serine proteases (plasmin and thrombin) infiltrate the brain, activating protease-activated receptors (PAR) and increasing the expression of N-methyl-D-aspartate receptors (NMDARs). This activation enhances glutamate-induced excitotoxicity, contributing to seizures.

Structural Changes of Brain Network

Epilepsy is increasingly understood as a disorder of the brain's entire functional network, with recent research focusing on neural network mechanisms. Late-onset epilepsy after stroke, often presenting as focal seizures, is linked to changes in these neural networks. Ischemia and hypoxia can cause significant neuronal damage, but the brain retains some capacity for regeneration, leading to the creation of new neurons that can integrate into existing neural pathways. However, abnormal activity in these newly formed networks can lead to seizures.

Astrocytic Proliferation

In the later stages of stroke, astrocytic proliferation contributes to brain damage and the development of acquired epilepsy. Reactive astrocytes form glial scars, altering their physiological function and affecting neural networks, which can lead to late-onset epilepsy.

In addition, reactive astrocytes are a key feature of late seizures after stroke, as they undergo morphological and functional changes. They impair glutamate homeostasis, increasing glutamate production and decreasing GABA synthesis, which lowers the seizure threshold and raises neuronal excitability. Additionally, reactive astrocytes alter the extracellular matrix, disrupting synaptic function and neuronal stability, and further promoting seizures.

Genetics and Genes

Around 30% of epileptic syndromes are hereditary, and over 500 genetic loci have been linked to epilepsy in humans and mice. Genetic factors such as the ALDH2, CD40, and TRPM6 polymorphisms contribute to the increased risk of seizures following a stroke, potentially offering targets for prediction and intervention.

Regional Hemodynamic Changes

Local cerebral hemodynamic changes can trigger seizures. Studies have shown increased local cerebral blood flow (CBF) and volume in patients with non-convulsive status epilepticus compared to those in the postictal state. Additionally, thrombolysis increases seizure incidence. Seizures during or after thrombolysis may indicate successful reperfusion, highlighting local hemodynamic changes as risk factors.

Risk Factors of Seizures and Epilepsy After Stroke

• Acute symptomatic epileptic seizures
• Cortical involvement
• Severity and etiology of stroke
• Age
• Stroke type (hemorrhagic vs. ischemic)
• When infarction or hemorrhage affects the anterior circulation
• Larger lesions

Treatment of Seizures and Epilepsy After Stroke

Antiepileptic drugs (AEDs) are the primary treatment for epilepsy across all age groups. First-line AEDs for focal and generalized seizures include carbamazepine, lamotrigine, sodium valproate, and topiramate. Carbamazepine shows a good correlation between dose and plasma concentration. Alternative monotherapies include phenytoin, phenobarbital, and clonazepam, with phenytoin being the most commonly used, especially in older patients. A key limitation of these AEDs is their potential to cause sedation.

1. Chen, J., et al. (2022). Pathogenesis of seizures and epilepsy after stroke. Acta Epileptologica, 4, 1-6.
2. Tanaka, T., et al. (2024). Pathophysiology, diagnosis, prognosis, and prevention of poststroke epilepsy: clinical and research implications. Neurology, 102(11), e209450.