Post-Stroke Seizures: Epidemiology and Risk Factors
Post – Stroke Seizures: A Comprehensive Review of Epidemiology, Pathophysiology, Risk Factors, Clinical Spectrum and Outcomes
Aparajit Ravikumar¹*, R.M. Bhoopathy¹, Anirban Laha¹, R. Mani²
- Department of Neurology, Tamil Nadu Government Multi Super Speciality Hospital, Omandurar, Chennai – 600002, Tamil Nadu, India.
- Senior Ophthalmologist & Dean, Tamil Nadu Government Multi Super Speciality Hospital, Omandurar, Chennai – 600002, Tamil Nadu, India.
OPEN ACCESS
PUBLISHED:31 October 2024
CITATION: Ravikumar, A., Bhoopathy, RM, et al., 2024. Post-Stroke Seizures: A Comprehensive Review of Epidemiology, Pathophysiology, Risk Factors, Clinical Spectrum and Outcomes. Medical Research Archives, [online] 12(10).
https://doi.org/10.18103/mra.v12i10.5768
COPYRIGHT: © 2024 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI https://doi.org/10.18103/mra.v12i10.5768
ISSN 2375-1924
ABSTRACT
Post-stroke seizure (PSS) represent a significant and often notable complication following cerebrovascular damage due to infarct and hemorrhage, that can affect stroke recovery and the long-term prognosis. This review aims to delineate the epidemiology, clinical spectrum, and outcomes of PSS through an extensive analysis of current literature. It is classified into two types based on the onset of occurrence following stroke, early-onset, occurring within the first seven days following stroke, and late-onset, which manifest beyond seven days after stroke. Early seizures have the same clinical course as acute symptomatic seizures, they rarely recur or require long-term antiepileptic drugs (AED’s). Conversely, late seizures are associated with a risk of recurrence similar to that of unprovoked seizures in a patient with a focal lesion, thereby requiring long-term administration of AED’s. The pathophysiology of PSS is multifaceted and involves a complex interplay of acute metabolic disturbances, excitotoxic neurotransmitter release causing neuronal hyperexcitability, and chronic neural network reorganization. Key risk factors include the type, location, and severity of the stroke, with cortical and hemorrhagic strokes being more prone to induce seizures. Clinically, PSS manifests predominantly as focal seizures, with some cases progressing to generalized seizures or status epilepticus. PSS is associated with poorer functional recovery, reduced quality of life, cognitive decline, increased morbidity, and a higher risk of developing epilepsy. Preventing stroke and PSS remains a cornerstone of any strategy to achieve optimal brain health. Early identification and appropriate management of PSS are crucial for minimizing their impact and thereby improving long-term outcomes for stroke survivors. Effective management includes the use of AED’s, secondary prevention strategies, comprehensive rehabilitation, and regular monitoring. Continued research and individualized treatment plans are essential to develop better preventive, diagnostic, and therapeutic strategies for PSS, ultimately enhancing the prognosis and wellbeing of those affected by strokes.
Keywords: post-stroke seizure, complication, stroke, morbidity, epilepsy, anti-epileptic drugs.
Introduction
Stroke is the most prevalent cause of seizures and epilepsy in elderly population¹. With an annual death toll of around 5.5 million, stroke continues to be the second most common cause of mortality worldwide and is the primary cause of disability worldwide, impacting 50% of survivors of stroke. Ischemic strokes generally represent around 80% of stroke occurrences, whereas hemorrhagic strokes account for about 20%²,³. The occurrences of stroke have surged by 50% in the last twenty years, showing a 70% rise in the incidence from 1990 to 2019⁴. The development of post-stroke seizure (PSS) affects 2% to 14% of those who survive an ischemic stroke and 10% to 20% of those who have suffered a hemorrhagic stroke⁵. The latency period for the onset of post-stroke seizure is inconsistent, yet 40% to 80% of the cases manifest within the first year following a stroke⁶. In addition to rising mortality and morbidity in stroke patients, post-stroke seizures leads to prolonged stay in the hospital and greater disability during discharge when compared to stroke patients without post-stroke seizure⁶. The occurrence of seizures shortly after a stroke can exacerbate metabolic stress and neuronal damage, leading to an increase in the size of infarct, higher mortality, and detrimental functional outcomes⁷,⁸. Repeated episodes of seizures can result in injuries, disrupt the cognitive function, hinder one’s ability to perform their activities of daily living (ADL), and adversely impact the quality of life⁹,¹⁰. This review encapsulates the current insights into post-stroke epileptogenesis, clinical spectrum, and treatment which includes both primary and secondary prophylactic measures, and suggests strategies to enhance research efforts.
Classification
Acute symptomatic seizures resulting from a stroke are strongly linked to the location and extent of brain damage. Consequently, a causal relationship can be established if the brain lesion responsible for the seizures is clearly identified and the seizure happens in close temporal proximity¹¹. The International League Against Epilepsy (ILAE) categorizes post-stroke seizures as early or late based on a 7-day threshold. According to this classification, seizures that occur within 7 days from the onset of stroke are considered early seizures, while those occurring 7 days after the onset of stroke are classified as late seizures¹². Early seizures are distinguished by amplified inflammatory responses, alterations in neuronal signalling associated with protein synthesis, enhanced release of excitatory neurotransmitters such as glutamate, ionic dysregulation, increased permeability of the blood-brain barrier (BBB), degradation of membrane phospholipids, liberation of free fatty acids, and heightened oxidative stress¹³,¹⁴. Additionally, the adjacent ischemic penumbra, which is characterized by its electrical irritability, serves as a zone of epileptogenesis¹⁵. Late seizures, in contrast are delineated by immutable alterations, including selective neuronal depletion, gliosis, chronic inflammation, neurodegeneration, angiogenesis, collateral synaptic arborization, and modifications in synaptic plasticity¹³. These modifications culminate in neuronal hyperexcitability, neuronal hypersynchrony, and an augmented propensity for seizures¹⁶. Thus, early seizures adhere to the trajectory of acute symptomatic seizures, while late seizures align with the progression of unprovoked seizures¹⁷,¹⁸,¹⁹. Hence, categorizing post-stroke seizures into early and late types is essential for differentiating between acute symptomatic and unprovoked seizures.
Epidemiology
The preponderance of strokes transpires in adults over 45 years of age, with up to 90% being ischemic and the remainder hemorrhagic. Stroke represents the most prevalent discernible etiology of acquired epilepsy in high-income nations²⁰,²¹. Epilepsy risk assessments following stroke have been thoroughly investigated, with findings varying according to study methodologies. In the general populace, the most representative estimates are derived from prospective longitudinal studies of large cohorts or register-based analyses. An incidence rate of post-stroke epilepsy of 6.4% was identified in both a population-based study in London, UK, and a nationwide registry in Sweden²²,²³. Post-stroke epilepsy (PSE) emerged in 3.8% of individuals within 5 years following the onset of their initial stroke in the Oxfordshire Community Stroke Project²⁴. Similarly, in the prospective Seizures After Stroke Study, which observed 1,897 patients for 9 months, post-stroke epilepsy developed in 2.5% of participants²⁵. Additionally, the Rochester study, encompassing 535 individuals with ischemic strokes, reported a 3.4% incidence of post-stroke epilepsy over a 5.5-year follow-up period²⁶. In adult demographics, approximately 70–85% of cerebrovascular maladies are ischemic, and the preponderance of post-stroke epilepsy cases results from arterial ischemic stroke²⁷. The most extended population-based longitudinal study conducted by Graham and associates disclosed that the 10-year prevalence of post-stroke epilepsy was 28.7% following total anterior circulation infarct, 13.4% following partial anterior circulation infarct, and 4.8% following posterior circulation infarct²².
Following an ischemic stroke, the highest risk for the initial unprovoked post-stroke seizure occurred during the first year of follow-up¹⁹,²⁸. During a follow-up period of 5 years, the average annual increase in risk for late seizures post ischemic stroke after the initial year was 1.5%²⁴. A further investigation disclosed that the probability of yearly incidence of seizures subsequent to a primary ischemic stroke is 6.3%, 2.4%, 1.3% after the first, second and third year following the stroke respectively and 0.3% henceforth²⁹. Registry derived data from a case-control investigation likewise implied that the likelihood of spontaneous seizure occurrence remains elevated for 7 years following an ischemic stroke, peaking during the initial year post stroke³⁰. Data accumulated over the past decade has highlighted the emergence of post-stroke epilepsy in younger adults¹⁹,²⁸,²⁹.
Moreover, within the Rochester cohort of ischemic stroke patients, the unequivocal risk of late-onset seizures post-ischemic stroke was analogous between individuals under 55 years of age and those exceeding 75 years of age²⁶. The minimal influence of age on the susceptibility to post-stroke epilepsy was similarly observed in two contemporary investigations³¹. Caveats also persist concerning the identification of seizures in the geriatric population (above 60 years), in whom ictal episodes may be less prevalent and seizure phenotypes are more challenging to discern compared to younger individuals (below 55 years)³². The diagnostic scrutiny is also expected to be more exhaustive in younger individuals with ischemic stroke compared to the elderly, and the elevated survival rates among younger cohorts may underpin the prevalence of late-onset seizures³³. The prevalence of acute symptomatic seizures and unprovoked seizures fluctuates across disparate studies, partly owing to heterogeneous research methodologies, divergent delineations of the temporal spans for acute symptomatic and unprovoked seizures, and inconsistent follow-up intervals. The occurrence of acute symptomatic seizures has been documented to range from 2% to 33%, however, it is consistently observed that over half of these seizures transpire within the initial 24 hours post-stroke¹⁶,²⁵. The prevalence of unprovoked seizures ranges from 3% to 67%. These seizures are more frequently observed between 8 and 12 months post-stroke, although unprovoked seizures can still manifest even a decade after the event of stroke¹⁶,²⁷.
Pathophysiology
In the context of ischemic stroke, early seizures are correlated with elevated extracellular potassium and glutamate levels, consequent to ischemic neuronal injury, thereby amplifying neuronal excitation. Conversely, late seizures arise from gliotic scarring within the cortex, dysregulation of the neurovascular unit, and perturbation of neuronal networks³⁴. In preclinical research, cerebrovascular accidents trigger inflammatory cascades that facilitate epileptogenesis. Stimulated astrocytes and microglia, alongside the secretion of proinflammatory cytokines (such as Interleukin [IL]-1β and High mobility group protein B1), exacerbate blood-brain barrier (BBB) compromise, leading to the release of albumin and activation of the Transforming growth factor (TGF)-β pathway, thus setting off a detrimental feedback loop³⁴. These investigations have exclusively explored the acute phase of stroke, thus leaving the mechanisms by which the progression to epileptogenesis is ambiguous.
Hemorrhagic stroke leads to the extravasation of albumin into the cerebral parenchyma, which triggers epileptogenesis through the activation of the transforming growth factor-β receptor on astrocytes. This phenomenon is orchestrated by a distinctive inflammatory milieu and the genesis of excitatory synapses³⁵. Pathogenic impact has also been ascribed to the extravasation of additional hematogenous substances, such as hemosiderin or iron³⁶. Post-stroke epilepsy is more prevalent in hemorrhagic than ischemic strokes, indicating the potential involvement of iron accumulation in post-stroke epileptogenesis³⁶. Iron is a micronutrient which is crucial for mitochondrial activity³⁶. In healthy individuals, approximately 4–5 grams of iron are sequestered primarily within erythrocytes and the liver. Iron within the cerebral milieu is meticulously regulated to sustain neuronal homeostasis³⁶. Stroke perturbs this balance, leading to iron deposition within the brain parenchyma (e.g., intracerebral hemorrhage or hemorrhagic transformation following ischemic stroke) or on the surface (e.g., subarachnoid hemorrhage), which is profoundly cytotoxic³⁶. The recently elucidated iron-dependent cellular demise, termed ferroptosis, is ascribed to lipid peroxidation instigated by the generation of reactive oxygen species. Excessive iron accumulation is observed in a range of neurologic pathologies, including epilepsy. Persistent perturbations in neuronal excitability may arise due to hemosiderin deposits, culminating in post-intracerebral hemorrhage (ICH) inflammation and gliotic changes³⁶.
Cortical superficial siderosis exhibits a robust correlation with post-stroke epilepsy³⁷. Furthermore, delayed seizures following intracerebral hemorrhage are linked specifically to lobar cerebral microbleeds and the APOE4 genotype, implying the concurrent presence of cerebral amyloid angiopathy pathology in post-stroke epilepsy³⁸. A recent investigation divulged that cortical superficial siderosis serves as a predisposing element for the onset of seizures in the context of cerebral amyloid angiopathy³⁹. Cortical superficial siderosis confined to the convex surfaces of the cerebral hemispheres and the supratentorial area may present as transient focal neurological events (TFNEs), i.e., amyloid episodes, which are predominantly recurrent, patterned, and brief (typically less than 30 minutes) with diverse clinical manifestations⁴⁰. Transient focal neurological episodes are observed in 34% of individuals with cerebral amyloid angiopathy and cortical superficial siderosis, frequently recurring in 53% of cases, with 4% progressing to generalized convulsions⁴⁰. Cortical superficial siderosis has the potential to provoke spontaneous convulsions in the absence of alternative causes, indicating its involvement in post-stroke epileptogenesis³⁶.
Risk Factors
Attributable to the diverse etiologies and pathologies, the engagement of cerebrovascular risk determinants is variegated. Nonetheless, substantial infarct volume, involvement of cortex, magnitude of cerebrovascular accident, hemorrhagic insult or infarct with hemorrhagic transformation, and premature convulsions are unequivocal prognosticators of post-stroke epilepsy³⁴,⁴¹. The incidence of acute convulsive episodes associated with hemorrhagic stroke surpasses that of ischemic cerebrovascular events (10–16% vs. 2–4%)²⁴,⁴²,⁴³. Ischemic infarctions accompanied by hemorrhagic conversion exhibit an elevated convulsion risk compared to isolated ischemic strokes⁴⁴. There exists an augmented frequency of post-stroke seizures epilepsy in instances involving the cortex, extensive infarction of anterior circulatory territory, severe cerebrovascular events with extensive lesions, and functional impairments⁴⁵,⁴⁶. Reperfusion insult may present as disruption of the blood–brain barrier, cortical excitation, and epileptic episodes⁴⁶. Cerebrovascular interventions, encompassing craniotomy, decompressive craniectomy, administration of intravenous alteplase, or endovascular therapy, are likewise regarded as post-stroke epilepsy predisposition factors. Nonetheless, this observation was not corroborated in other investigations, including extensive population-based stroke registries and meticulously designed multicenter studies, which found no association between early convulsions or post-stroke epilepsy and reperfusion therapies, whether intravenous thrombolysis alone or in conjunction with mechanical thrombectomy⁴⁷. Variations in the intensity or site of hemorrhagic transformation and the permeability of recanalized vessels may influence the manifestation of convulsions subsequent to ischemic cerebrovascular incidents⁴⁸. A comprehensive meta-analysis encompassing 51 investigations elucidated that irrespective of whether individuals afflicted by ischemic stroke receive thrombolysis or thrombectomy, hemorrhagic transformation exhibited a pronounced correlation with the onset of early seizures and post-stroke epilepsy⁴⁸. Recanalization therapy in individuals afflicted by stroke may partially salvage moribund neurons, resulting in the formation of sporadic islands of the cortex⁴⁹. These surviving residual islands could conceivably influence epileptogenesis in conjunction with hemorrhagic transformation⁴⁹. Acute symptomatic seizures may be precipitated by direct and instantaneous factors, such as metabolic disturbances, infections of the central nervous system, septicemia, physical injuries, pharmacological substances, and ethanol consumption⁵⁰,⁵¹. Seizures that are acute and symptomatic, caused by metabolic imbalances, are linked to the rate at which the metabolic condition worsens; quicker rate of decline increases the likelihood of seizures⁵². Symptomatic convulsions stemming from a central nervous system infection may still be classified as acute symptomatic seizures beyond 7 days, contingent upon the clinical progression or laboratory diagnostics, as the delineation remains ambiguous⁵³. Septicemia can precipitate encephalopathy, which engenders convulsive or nonconvulsive seizures by activating the neural circuits that facilitate seizure activity⁵³. Acute symptomatic seizures attributable to alcohol withdrawal should be contemplated in an individual with a background of substantial ethanol consumption who manifests generalized tonic–clonic seizures following a period of alcohol abstinence lasting 7–48 hours⁵¹. Alterations linked to small vessel pathology, encompassing leukoaraiosis and lobar cerebral microbleeds, are correlated with post-stroke epilepsy³⁵,⁵⁴. Cortical superficial siderosis exhibits a robust correlation with post-stroke epilepsy, irrespective of whether the cerebrovascular insult is ischemic or hemorrhagic, and is marked by the deposition of hemosiderin in the pial or subpial strata of the central nervous system³⁷. In subarachnoid hemorrhage (SAH), cortical superficial siderosis bears a significant association with post-stroke epilepsy, irrespective of location of the aneurysm, intensity of SAH, or cerebrovascular symptoms⁵⁵. Additionally, an extension of intracerebral hemorrhage into the subarachnoid space is notably linked to the occurrence of early seizures, regardless of the site of hematoma⁵⁶. In adults, Jungehulsing et al., discerned that hypertension and the intensity of cerebrovascular insult were substantial prognosticators for post-stroke epilepsy⁵⁷. Remarkably, as per the findings of Devuyst et al., an augmented concentration of cholesterol might exert a salutary effect on convulsions and ischemic cerebrovascular events⁵⁸. Furthermore, Roivainen et al., observed that nicotine use, chronic alcohol indulgence, and pre-stroke infections were more pronounced in individuals experiencing late post-stroke seizures.
compared to those with acute symptomatic convulsions (up to 7 days following the onset of the stroke)²⁹. Remarkably intriguing findings were elucidated by Cordonnier et al., who established that antecedent cognitive impairment was independently associated with the onset of delayed convulsions, but not with early epileptic episodes⁵⁹. This observation might be elucidated by a potential disruption in glutamatergic pathways among individuals with dementia. Hesdorffer et al., discerned that the propensity for subsequent spontaneous unprovoked seizures is elevated in instances of late post-stroke seizures compared to early symptomatic epileptic episodes¹⁷. The outcomes of a Korean investigation revealed that certain determinants of elevated susceptibility to a secondary convulsion following an initial episode may materialize; individuals predominantly at risk for a subsequent seizure during follow-up are typified by male sex, age under 65 years, extensive ischemic lesions, and focal seizures in clinical manifestations⁶⁰. This insight could prove beneficial in formulating personalized treatment strategies following the initial seizure. Recent studies also indicate that intravenous recombinant tissue plasminogen activator (rTPA) therapy, sanctioned for the management of acute cerebrovascular accident, may constitute a risk factor for subsequent post-stroke epilepsy due to its potential neurotoxic effects⁶¹. The utilization of antidepressants was a notable predisposing factor for late post-stroke seizures within the Finnish cohort, whereas the administration of antipsychotic or anxiolytic pharmacological agents was characteristic of patients exhibiting both acute symptomatic seizure and late post-stroke seizure²⁹. As a matter of fact, a familial antecedent of epilepsy is ought to be considered as a contributing risk factor for post-stroke epilepsy, given that genetic predispositions play a role in epileptogenesis⁶.
Clinical Spectrum
Post-stroke seizures predominantly exhibit localization specific seizure semiology, contingent upon the precise locus of the cerebral lesion. Approximately one-third of all seizures are generalized tonic-clonic seizures (GTCS), while the remaining two-thirds present as focal seizures, with status epilepticus noted in 9% of instances⁶²,⁶³. Focal seizures are prevalent in the acute phase of seizure onset, whereas generalized seizures are more frequent in the chronic phase⁶². Among patients with ischemic cerebrovascular accidents resulting from occlusion of large vessels, seizures emerging within the initial 24 hours were chiefly focal convulsions or GTCS, whereas seizures accompanied by impaired awareness tend to occur more frequently beyond 24 hours⁶⁴. Conrad et al., demonstrated that in nearly 41% of post-stroke seizure subjects, seizures were categorized as partial (predominantly simple partial), while 57% of individuals experienced generalized seizures. Nonetheless, there remain cases where the specific type of convulsion remains indeterminate⁶⁵. In instances of post-stroke seizures in the pediatric population, Kopyta et al., revealed that every analysed juvenile subject with post-stroke seizures experienced convulsions, which were focal in character. Nevertheless, in 40% of these cases, the convulsions were secondary generalized⁶⁶. In the investigation conducted by Pilarska and Lemka, 7% of the scrutinized pediatric patients with acute ischemic stroke exhibited early post-stroke seizure, that were generalized tonic & clonic, manifesting within the initial 24 hours post cerebrovascular accident⁶⁷. The incidence rates of epilepsy, stratified by age, have shifted, exhibiting a reduction in younger demographics and a surge among individuals over 60 years⁶⁸. Cerebrovascular accidents (CVA) emerge as the foremost etiology of epilepsy in patients beyond 60 years of age, with an incidence ranging from 2 to 4% as reported in various studies⁶⁹. Early seizures manifest considerably more frequently in individuals with hemorrhagic strokes and are associated with a dismal prognosis, accompanied by elevated mortality rate in the hospital, however, the recurrence rate remains minimal. Late seizures predominantly emerge between 6 to 24 months post stroke, with a heightened recurrence rate⁷⁰.
The delayed onset of the initial convulsion serves as an autonomous predisposing factor for epilepsy following an ischemic stroke, but not subsequent to hemorrhagic stroke⁷¹. About 20% of convulsions occurring in individuals with a prior cerebral infarction may subsequently manifest as a clinical indication of a new cerebrovascular event⁷². Arboix et al., postulated that individuals at the greatest risk of manifesting epileptic seizures are elderly patients with extensive hemorrhagic infarctions in the parietal lobe, who may warrant prophylactic management with antiepileptic agents for a brief duration⁷². Epilepsy seldom constitutes a major issue in young individuals recovering from cryptogenic ischemic strokes⁶⁸. Dhanuka et al., discovered a more youthful median age at the initial convulsion post cerebrovascular accident (mean 45.41 years), despite enrolling a diverse cohort (age ranging between 5 months to 76 years)⁷³. In this compilation, the males were observed with greater frequency relative to females, which were consistent with antecedent regional and global studies⁷³. The majority of post-stroke seizures exhibit a focal onset and predominantly fall into the category of simple partial seizures, which is succeeded by primary generalized seizures. Complex partial seizures (CPS) are less prevalent, with the highest documented incidence being 24% of all post-stroke seizures⁷⁴,⁷⁵. In the investigation undertaken by Kamble et al., the predominant category of convulsion was generalized, in contrast to partial or secondary generalized seizures typically anticipated in symptomatic epilepsy such as post-stroke seizures⁷⁶. This finding diverges from earlier data indicating a predominance of partial seizures in post-stroke seizures, which may be attributable to the low educational attainment of the study cohort, potentially leading to a misclassification of partial or secondary generalized seizures as generalized⁷⁵. In an investigation from India conducted by Dhanuka et al., 60% of post-cerebrovascular accident patients exhibited recurrent convulsions⁷³. Nonetheless, certain inquiries revealed lower frequencies of recurrent seizures, such as in the prospective multicentric global investigation Seizures After Stroke Study Group (SASS), where 28% of participants experienced multiple convulsions⁷⁷. The prevalence of Status Epilepticus varies across studies. Milandre et al., documented an incidence of 14% among patients with initial post-stroke epilepsy, whereas Lo et al., reported a prevalence of 10%⁷⁸,⁷⁹.
Outcomes
In advanced nations, no fewer than one in ten cerebrovascular accident survivors will experience epilepsy⁸⁰. Nevertheless, despite the elevated risk of convulsions and epilepsy following a stroke, the American Heart Association does not advocate for prophylactic intervention with antiepileptic drugs (AEDs) in these patients⁸¹. The potential utility of certain novel-generation AEDs in thwarting epileptogenesis is currently under speculation. In a rodent paradigm of epilepsy, levetiracetam attenuated gliosis within the hippocampus and piriform cortex⁸². Subsequently, Perampanel, an innovative selective, non-competitive AMPA glutamate receptor antagonist, was proposed as a prospective impediment of epileptogenesis by mitigating glutamatergic excitotoxicity⁸³. Moreover, aspirin and rapamycin, owing to their anti-inflammatory properties, are contemplated for their potential in the prophylaxis of post-stroke epilepsy⁸⁴,⁸⁵. Prophylactic administration of primary antiepileptic drugs is not endorsed, as its efficacy in mitigating acute symptomatic or idiopathic convulsions or enhancing functional outcomes and survival rates remains inadequately substantiated⁴⁵. Short-term AEDs therapy, spanning 1 to 4 weeks, is generally employed for acute symptomatic seizures due to the minimal risk of recurrence⁴⁵. European directives do not advocate for secondary prophylactic AEDs intervention for post-stroke seizures. Individuals undergoing a solitary acute symptomatic convulsion within 7 days possess a 10
20% probability of encountering subsequent acute symptomatic seizures, hence secondary AEDs prophylaxis is deemed unnecessary⁴⁵,⁸⁶. Notwithstanding the comparatively modest recurrence rate, ephemeral antiepileptic agent therapy is employed in individuals with a pathophysiological substrate. Antiepileptic agents may attenuate neuronal excitotoxicity, peri-infarct depolarization, and inflammatory cascades⁸⁷. Certain investigations advocate for transient antiepileptic agent therapy in nascent seizures to mitigate the proclivity for clinical deterioration during the acute phase. This strategy is predicated on pathophysiological considerations, encompassing diminished cerebral perfusion states such as stroke with hemodynamically significant stenosis, cerebral edema, and vasospasm subsequent to SAH⁸⁸,⁸⁹. Nevertheless, guidelines advocate for the gradual reduction of antiepileptic agent therapy following the acute phase due to the low 10-year probability of idiopathic unprovoked convulsion occurrence post a solitary post-stroke seizure which constitutes about 30%⁴⁵. The likelihood of recurrent idiopathic post-stroke seizures within a decade is elevated (70%), consequently prophylaxis with secondary AEDs is endorsed¹⁷,⁴⁵. Prolonged AEDs administration is advised for post-cerebrovascular unprovoked idiopathic seizures due to the substantial likelihood of recurrence of seizure upon cessation of therapy which estimates ≥50%¹⁷,⁴⁵. In summation, protracted AEDs utilization is contraindicated, except in cases of idiopathic unprovoked post-stroke seizures. Nonetheless, it may be employed transiently during the acute phase, contingent upon the patient’s condition, in alignment with the conceptualization and therapeutic paradigm for epilepsy delineated by the International League Against Epilepsy (ILAE)¹¹,⁹⁰. A multicentric randomized controlled trial posited that lamotrigine exhibits superior efficacy as a primary therapeutic agent for individuals with focal epilepsy compared to zonisamide or levetiracetam⁹¹. Concerning the management of post-stroke seizures, the efficacies of lamotrigine, levetiracetam, and carbamazepine (extended-release) were analogous, although lamotrigine and levetiracetam were deemed more tolerable relative to carbamazepine⁹²,⁹³. The deployment of a vigorous statin regimen in individuals afflicted by cerebrovascular accidents has been reported to mitigate the incidence of both early and delayed post-stroke seizures. Additionally, prolonged administration of statins for durations exceeding 2 years resulted in a diminution of the risk for post-stroke epilepsy, irrespective of whether the statin therapy was commenced pre or post the event of cerebrovascular accident⁹⁴,⁹⁵. The exact anticonvulsant mechanism of statins remains enigmatic, though numerous hypotheses have been posited. Primarily, neuroinflammation consequent to cerebrovascular accidents amplifies neuronal excitability, precipitating the release of aberrant neurotransmitters through augmented blood-brain barrier (BBB) permeability, thereby inducing seizures via the exacerbation of cerebral hypoxia⁹⁶. Statins mitigate convulsions by deploying anti-inflammatory effects, including the modulation of BBB permeability, regulation of endothelial nitric oxide synthase, attenuation of proinflammatory gene expression, inhibition of pro-inflammatory cytokines and reactive oxygen species, and suppression of lipid peroxidation⁹⁷. Although acute ischemia augments glutamate concentrations, statins attenuate the excitotoxicity of glutamate by diminishing the activity and uptake of N-methyl-D-aspartate (NMDA) receptors and modulating intracellular calcium concentrations⁹⁶,⁹⁸,⁹⁹. Apoptosis is precipitated by Bax, whereas Bcl suppresses it. Statins influence apoptotic cascades linked to these genes and enhance neuronal viability, thus forestalling epilepsy¹³. As per study conducted by Tanaka et al., 33% of medical facilities dispense AEDs following the initial late convulsion, whereas 88% prescribe AEDs after a subsequent episode³. An exception pertains to patients exhibiting status epilepticus as their initial epileptic presentation⁹⁰. Although the prompt deployment of anti-epileptic drugs in post-CVA individuals does not alter the etiology or prognostic trajectory of the affliction, it may avert the manifestation of a subsequent convulsion, particularly given the substantial risk of recurrence following an initial late-onset post-stroke seizures, which is approximated to impact roughly one-third of patients⁶⁰,¹⁰⁰.
Conversely, in the investigation conducted by Ahangar et al., phenobarbital or phenytoin was administered at a nascent stage, specifically to a subject presenting with both early- and late-onset post-stroke seizures¹⁰¹. The researchers attribute the subsequently diminished frequency of recurrent convulsions to this precocious incorporation of anticonvulsant therapy¹⁰¹. According to studies, anticonvulsant therapy should be initiated subsequent to the initial late onset post-stroke seizure¹⁰². Gabapentin, administered at a daily dosage of 900–1800 mg, is one of the advocated pharmacological agents for treating adults following the first late-onset convulsion¹⁰². Monitoring patients over a span of 30 months, the investigators noted a recurrence rate of approximately 18% within the cohort. Adverse effects necessitating cessation of the medication were documented in 3% of the subjects¹⁰². Oros et al. elucidated that recurrent epileptic paroxysms afflicted 27% of individuals with acute ischemic stroke (AIS) who were administered anticonvulsants within 1 year post initial post-stroke seizure, whereas nearly 54% of those who abstained from antiepileptic intervention experienced repeated convulsive episodes¹⁰³. In the majority of cases, post-stroke epilepsy is efficaciously managed with monotherapeutic regimens¹⁰⁴. Given that the convulsions in post-stroke epilepsy are inherently focal, the initial pharmacological intervention in European adults often involves carbamazepine and gabapentin, whereas in the United States, the preferred first-line agents are phenytoin and gabapentin¹⁰³,¹⁰⁵. Nevertheless, in Japanese population afflicted with post-stroke epilepsy, the dispensation of valproic acid as the foremost pharmacological remedy is more ubiquitous owing to the fact that the second-generation anticonvulsant agents remain unratified within this jurisdiction¹⁰⁶. In the stochastic noncontrolled trial by Gilard et al., juxtaposing the potency and adverse reactions of lamotrigine and carbamazepine, the former exhibited superior efficacy, with subjects administered lamotrigine reporting a diminished incidence of adverse reactions¹⁰⁷. However, comparing the efficacy between levetiracetam and carbamazepine, it did not elucidate any discernible pre-eminence of either pharmacological agent, although levetiracetam demonstrated enhanced tolerability¹⁰⁸. As per Billinghurst et al., convulsive episodes in pediatric AIS cases were predominantly managed with levetiracetam, phenobarbital and phenytoin (62%, 46% and 8%, correspondingly). Approximately a quarter of the cohort necessitated polytherapy with multiple anticonvulsants at the point of discharge¹⁰⁹. The prognostication in adult-onset post-stroke epilepsy appears markedly propitious. Stephen et al., surveyed a cohort of individuals afflicted with post-stroke epilepsy over a biennial duration, the majority necessitated merely a singular AED, and by the culmination of the second annum of scrutiny, up to 67% of the cohort attained seizure abeyance¹¹⁰.
Conclusion
Post-stroke seizures (PSS) constitute prevalent sequelae of apoplexy. It is crucial to methodically scrutinize, assess, categorize, and administer interventions, differentiating them from anomalous movement disorders, syncopal events and psychogenic non-epileptic seizures (PNES) predicated based on the semiology. A meticulous approach and identification of etiological factors beyond cerebrovascular structural aberrations that may precipitate acute symptomatic seizures are essential. Upon confirmation of a post-stroke seizure, we can adeptly manage patients, enhance their prognostic outlook by ascertaining whether the episode is early or late, and devise a therapeutic regimen tailored to their specific
pathophysiological state. This elucidates the intricate etiology of post-stroke epilepsy and its prognostication. Consequently, the greater the erudition concerning post-stroke epilepsy, the more sophisticated, exacting, and potentially bespoke interventions stand to be actualized.
Conflict of Interest:
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Funding Statement:
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Acknowledgements:
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References
1. Lühdorf K, Jensen LK, Plesner AM. Etiology of seizures in the elderly. Epilepsia. 1986;27(4):458-463.
2. Donkor ES. Stroke in the 21st Century: A Snapshot of the Burden, Epidemiology, and Quality of Life. Stroke Res Treat. 2018;2018: 3238165. Published 2018 Nov 27.
3. Krishnamurthi RV, Feigin VL, Forouzanfar MH, et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet Glob Health. 2013;1(5):e259-e281.
4. Feigin VL, Brainin M, Norrving B, et al. World Stroke Organization (WSO): Global Stroke Fact Sheet 2022 [published correction appears in Int J Stroke. 2022 Apr;17(4):478. doi: 10.1177/1747493 0221080343]. Int J Stroke. 2022;17(1):18-29.
5. Pitkänen A, Roivainen R, Lukasiuk K. Development of epilepsy after ischaemic stroke. Lancet Neurol. 2016;15(2):185-197.
6. Sarecka-Hujar B, Kopyta I. Poststroke epilepsy: current perspectives on diagnosis and treatment. Neuropsychiatr Dis Treat. 2018;15:95-103. Published 2018 Dec 24.
7. Brondani R, de Almeida AG, Cherubini PA, et al. Risk Factors for Epilepsy After Thrombolysis for Ischemic Stroke: A Cohort Study. Front Neurol. 2020;10:1256. Published 2020 Jan 23.
8. Jung S, Schindler K, Findling O, et al. Adverse effect of early epileptic seizures in patients receiving endovascular therapy for acute stroke. Stroke. 2012;43(6):1584-1590.
9. Baranowski CJ. The quality of life of older adults with epilepsy: A systematic review. Seizure. 2018; 60:190-197.
10. Verducci C, Hussain F, Donner E, et al. SUDEP in the North American SUDEP Registry: The full spectrum of epilepsies. Neurology. 2019;93(3): e227-e236.
11. Mauritz M, Hirsch LJ, Camfield P, et al. Acute symptomatic seizures: an educational, evidence-based review. Epileptic Disord. 2022;24(1):26-49.
12. Guidelines for epidemiologic studies on epilepsy. Commission on Epidemiology and Prognosis, International League Against Epilepsy. Epilepsia. 1993;34(4):592-596.
13. Feyissa AM, Hasan TF, Meschia JF. Stroke-related epilepsy. Eur J Neurol. 2019;26(1):18-e3.
14. Karhunen H, Jolkkonen J, Sivenius J, Pitkänen A. Epileptogenesis after experimental focal cerebral ischemia. Neurochem Res. 2005;30(12):1529-1542.
15. Hameed, Sajid; Hakeem, Haris; and Wasay, Mohammad (2019) “Post-stroke seizures: a clinically oriented Analysis,” Pakistan Journal of Neurological Sciences (PJNS): Vol. 14: Iss. 3, Article 6.
16. Xu MY. Poststroke seizure: optimising its management. Stroke Vasc Neurol. 2018;4(1):48-56. Published 2018 Dec 9.
17. Hesdorffer DC, Benn EK, Cascino GD, Hauser WA. Is a first acute symptomatic seizure epilepsy? Mortality and risk for recurrent seizure. Epilepsia. 2009;50(5):1102-1108.
18. Alberti A, Paciaroni M, Caso V, Venti M, Palmerini F, Agnelli G. Early seizures in patients with acute stroke: frequency, predictive factors, and effect on clinical outcome. Vasc Health Risk Manag. 2008;4(3):715-720.
19. Lee JC, Lin KL, Wang HS, et al. Seizures in childhood ischemic stroke in Taiwan. Brain Dev. 2009;31(4):294-299.
20. Béjot Y, Bailly H, Durier J, Giroud M. Epidemiology of stroke in Europe and trends for the 21st century. Presse Med. 2016;45(12 Pt 2):e391-e398.
21. Forsgren L, Beghi E, Oun A, Sillanpää M. The epidemiology of epilepsy in Europe – a systematic review. Eur J Neurol. 2005;12(4):245-253.
22. Graham NS, Crichton S, Koutroumanidis M, Wolfe CD, Rudd AG. Incidence and associations of poststroke epilepsy: the prospective South London Stroke Register. Stroke. 2013;44(3):605-611.
23. Zelano J. Poststroke epilepsy: update and future directions. Ther Adv Neurol Disord. 2016;9 (5):424-435.
24. Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C. Epileptic seizures after a first stroke: the Oxfordshire Community Stroke Project. BMJ. 1997;315(7122):1582-1587.
25. Bladin CF, Alexandrov AV, Bellavance A, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol. 2000;57(11):1617-1622.
26. So EL, Annegers JF, Hauser WA, O’Brien PC, Whisnant JP. Population-based study of seizure disorders after cerebral infarction. Neurology. 1996;46(2):350-355.
27. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8 (4):355-369.
28. Hsu CJ, Weng WC, Peng SS, Lee WT. Early-onset seizures are correlated with late-onset seizures in children with arterial ischemic stroke. Stroke. 2014;45(4):1161-1163.
29. Roivainen R, Haapaniemi E, Putaala J, Kaste M, Tatlisumak T. Young adult ischaemic stroke related acute symptomatic and late seizures: risk factors. Eur J Neurol. 2013;20(9):1247-1255.
30. Adelöw C, Andersson T, Ahlbom A, Tomson T. Prior hospitalization for stroke, diabetes, myocardial infarction, and subsequent risk of unprovoked seizures. Epilepsia. 2011;52(2):301-307.
31. Lossius MI, Rønning OM, Slapø GD, Mowinckel P, Gjerstad L. Poststroke epilepsy: occurrence and predictors–a long-term prospective controlled study (Akershus Stroke Study). Epilepsia. 2005;46 (8):1246-1251.
32. Cloyd J, Hauser W, Towne A, et al. Epidemiological and medical aspects of epilepsy in the elderly. Epilepsy Res. 2006;68 Suppl 1:S39-S48.
33. Pitkänen A, Roivainen R, Lukasiuk K. Development of epilepsy after ischaemic stroke. Lancet Neurol. 2016;15(2):185-197.
34. Tanaka T, Ihara M. Post-stroke epilepsy. Neurochem Int. 2017;107:219-228.
35. Cacheaux LP, Ivens S, David Y, et al. Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. J Neurosci. 2009;29(28):8927-8935.
36. Tanaka T, Ihara M, Fukuma K, et al. Pathophysiology, Diagnosis, Prognosis, and Prevention of Poststroke Epilepsy: Clinical and Research Implications. Neurology. 2024;102(11):e209450.
37. Tanaka T, Fukuma K, Abe S, et al. Association of Cortical Superficial Siderosis with Post-Stroke Epilepsy. Ann Neurol. 2023;93(2):357-370.
38. Biffi A, Rattani A, Anderson CD, et al. Delayed seizures after intracerebral haemorrhage. Brain. 2016;139(Pt 10):2694-2705.
39. Tabaee Damavandi P, Storti B, Fabin N, Bianchi E, Ferrarese C, DiFrancesco JC. Epilepsy in cerebral amyloid angiopathy: an observational retrospective study of a large population. Epilepsia. 2023;64(2):500-510.
40. Lummel N, Wollenweber FA, Demaerel P, et al. Clinical spectrum, underlying etiologies and radiological characteristics of cortical superficial siderosis. J Neurol. 2015;262(6):1455-1462.
41. Zelano J, Holtkamp M, Agarwal N, Lattanzi S, Trinka E, Brigo F. How to diagnose and treat post-stroke seizures and epilepsy. Epileptic Disord. 2020;22(3):252-263.
42. Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia. 2010;51(4):671-675.
43. Procaccianti G, Zaniboni A, Rondelli F, Crisci M, Sacquegna T. Seizures in acute stroke: incidence, risk factors and prognosis. Neuroepidemiology. 2012;39(1):45-50.
44. Beghi E, D’Alessandro R, Beretta S, et al. Incidence and predictors of acute symptomatic seizures after stroke. Neurology. 2011;77(20):1785-1793.
45. Holtkamp M, Beghi E, Benninger F, et al. European Stroke Organisation guidelines for the management of post-stroke seizures and epilepsy. Eur Stroke J. 2017;2(2):103-115.
46. Hafeez F, Razzaq MA, Levine RL, Ramirez MA. Reperfusion seizures: a manifestation of cerebral reperfusion injury after administration of recombinant tissue plasminogen activator for acute ischemic stroke. J Stroke Cerebrovasc Dis. 2007;16 (6):273-277.
47. Ferreira-Atuesta C, Döhler N, Erdélyi-Canavese B, et al. Seizures after Ischemic Stroke: A Matched Multicenter Study. Ann Neurol. 2021;90(5):808-820.
48. He J, Fu F, Zhang W, Zhan Z, Cheng Z. Prognostic significance of the clinical and radiological haemorrhagic transformation subtypes in acute ischaemic stroke: A systematic review and meta-analysis. Eur J Neurol. 2022;29(11):3449-3459.
49. Bentes C, Martins H, Peralta AR, et al. Early EEG predicts poststroke epilepsy. Epilepsia Open. 2018;3(2):203-212.
50. Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia. 2010;51(4):671-675.
51. McLauchlan DJ, Powell R. Acute symptomatic seizures [published correction appears in Pract Neurol. 2012 Aug;12(4):279]. Pract Neurol. 2012; 12(3):154-165.
52. Nardone R, Brigo F, Trinka E. Acute Symptomatic Seizures Caused by Electrolyte Disturbances. J Clin Neurol. 2016;12(1):21-33.
53. Alessandri F, Badenes R, Bilotta F. Seizures and Sepsis: A Narrative Review. J Clin Med. 2021 ;10(5):1041.
54. Pitkänen A, Roivainen R, Lukasiuk K. Development of epilepsy after ischaemic stroke. Lancet Neurol. 2016;15(2):185-197.
55. Hirano T, Enatsu R, Iihoshi S, et al. Effects of Hemosiderosis on Epilepsy Following Subarachnoid Hemorrhage. Neurol Med Chir (Tokyo). 2019;59 (1):27-32.
56. Guth JC, Gerard EE, Nemeth AJ, et al. Subarachnoid extension of hemorrhage is associated with early seizures in primary intracerebral hemorrhage. J Stroke Cerebrovasc Dis. 2014;23(10):2809-2813.
57. Jungehulsing GJ, Heuschmann PU, Holtkamp M, Schwab S, Kolominsky-Rabas PL. Incidence and predictors of post-stroke epilepsy. Acta Neurol Scand. 2013;127(6):427-430.
58. Devuyst G, Karapanayiotides T, Hottinger I, Van Melle G, Bogousslavsky J. Prodromal and early epileptic seizures in acute stroke: does higher serum cholesterol protect?. Neurology. 2003;61 (2):249-252.
59. Cordonnier C, Hénon H, Derambure P, Pasquier F, Leys D. Influence of pre-existing dementia on the risk of post-stroke epileptic seizures. J Neurol Neurosurg Psychiatry. 2005;76 (12):1649-1653.
60. Kim HJ, Park KD, Choi KG, Lee HW. Clinical predictors of seizure recurrence after the first post-ischemic stroke seizure [published correction appears in BMC Neurol. 2017 May 4;17(1):84.
61. Naylor J, Thevathasan A, Churilov L, et al. Association between different acute stroke therapies and development of post stroke seizures. BMC Neurol. 2018;18(1):61.
62. Myint PK, Staufenberg EF, Sabanathan K. Post-stroke seizure and post-stroke epilepsy. Postgrad Med J. 2006;82(971):568-572.
63. Rumbach L, Sablot D, Berger E, Tatu L, Vuillier F, Moulin T. Status epilepticus in stroke: report on a hospital-based stroke cohort. Neurology. 2000;54(2):350-354.
64. Tako LM, Strzelczyk A, Rosenow F, et al. Predictive Factors of Acute Symptomatic Seizures in Patients With Ischemic Stroke Due to Large Vessel Occlusion. Front Neurol. 2022;13:894173.
65. Conrad J, Pawlowski M, Dogan M, Kovac S, Ritter MA, Evers S. Seizures after cerebrovascular events: risk factors and clinical features. Seizure. 2013;22(4):275-282.
66. Kopyta I, Sarecka-Hujar B, Skrzypek M. Post-stroke epilepsy in Polish paediatric patients. Dev Med Child Neurol. 2015;57(9):821-828.
67. Pilarska E, Lemka M. Epileptic seizures and epilepsy in ischemic stroke in children. Neurol Dziec. 2007;16:23–27.
68. Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol. 2003;16(2):165-170.
69. Benbir G, Ince B, Bozluolcay M. The epidemiology of post-stroke epilepsy according to stroke subtypes. Acta Neurol Scand. 2006;114(1):8-12.
70. De Reuck JL. Stroke-related seizures and epilepsy. Neurol Neurochir Pol. 2007;41(2):144-149.
71. Bladin CF, Alexandrov AV, Bellavance A, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol. 2000;57(11):1617-1622.
72. Arboix A, Comes E, Massons J, García L, Oliveres M. Relevance of early seizures for in-hospital mortality in acute cerebrovascular disease. Neurology. 1996;47(6):1429-1435.
73. Dhanuka AK, Misra UK, Kalita J. Seizures after stroke : a prospective clinical study. Neurol India. 2001;49(1):33-36.
74. Sung CY, Chu NS. Epileptic seizures in thrombotic stroke. J Neurol. 1990;237(3):166-170.
75. Gupta SR, Naheedy MH, Elias D, Rubino FA. Postinfarction seizures. A clinical study. Stroke. 1988;19(12):1477-1481.
76. Kamble S, Srivastava T, Sardana V, Maheshwari D, Bhushan B, Ojha P, Clinical and radiological profile of post-Stroke seizures. IP Indian J Neurosci 2017;3():8-12
77. Procaccianti G, Zaniboni A, Rondelli F, Crisci M, Sacquegna T. Seizures in acute stroke: incidence, risk factors and prognosis. Neuroepidemiology. 2012;39(1):45-50.
78. Milandre L, Broca P, Sambuc R, Khalil R. Les crises épileptiques au cours et au décours des accidents cérébrovasculaires. Analyse clinique de 78 cas [Epileptic crisis during and after cerebrovascular diseases. A clinical analysis of 78 cases]. Rev Neurol (Paris). 1992;148(12):767-772.
79. Lo YK, Yiu CH, Hu HH, Su MS, Laeuchli SC. Frequency and characteristics of early seizures in Chinese acute stroke. Acta Neurol Scand. 1994;90 (2):83-85.
80. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia. 1993; 34(3):453-468.
81. Winstein CJ, Stein J, Arena R, et al. Guidelines for Adult Stroke Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association [published correction appears in Stroke. 2017 Feb;48(2):e78.
82. Kim JE, Choi HC, Song HK, et al. Levetiracetam inhibits interleukin-1 beta inflammatory responses in the hippocampus and piriform cortex of epileptic rats. Neurosci Lett. 2010;471(2):94-99.
83. Ceolin L, Bortolotto ZA, Bannister N, Collingridge GL, Lodge D, Volianskis A. A novel anti-epileptic agent, perampanel, selectively inhibits AMPA receptor-mediated synaptic transmission in the hippocampus. Neurochem Int. 2012;61(4):517-522.
84. Sunnen CN, Brewster AL, Lugo JN, et al. Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice. Epilepsia. 2011;52(11):2065-2075.
85. Ma L, Cui XL, Wang Y, et al. Aspirin attenuates spontaneous recurrent seizures and inhibits hippocampal neuronal loss, mossy fiber sprouting and aberrant neurogenesis following pilocarpine-induced status epilepticus in rats. Brain Res. 2012;1469:103-113.
86. Leung T, Leung H, Soo YO, Mok VC, Wong KS. The prognosis of acute symptomatic seizures after ischaemic stroke. J Neurol Neurosurg Psychiatry. 2017;88(1):86-94.
87. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22(9):391-397.
88. Galovic M, Ferreira-Atuesta C, Abraira L, et al. Seizures and Epilepsy After Stroke: Epidemiology, Biomarkers and Management. Drugs Aging. 2021; 38(4):285-299.
89. Zelano J, Holtkamp M, Agarwal N, Lattanzi S, Trinka E, Brigo F. How to diagnose and treat post-stroke seizures and epilepsy. Epileptic Disord. 2020;22(3):252-263.
90. Beleza P. Acute symptomatic seizures: a clinically oriented review. Neurologist. 2012;18(3):109-119.
91. Marson A, Burnside G, Appleton R, et al. The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial [published correction appears in Lancet. 2021 May 15;397(10287):1808.
92. Bekelaar K, van Tuijl JH, van Raak EPM, van Oostenbrugge RJ, Aldenkamp AP, Rouhl RPW. Medication use in poststroke epilepsy: A descriptive study on switching of antiepileptic drug treatment. Epilepsy Behav. 2020;104(Pt B):106434.
93. Xu MY. Poststroke seizure: optimising its management. Stroke Vasc Neurol. 2018;4(1):48-56.
94. Li Y, Zhang B, Zhang L, Xie D, Li Y. Efficacy of Statin therapy in post-stroke seizure prophylaxis: Clues from an observational study of routine secondary prevention treatment. Seizure. 2019;71:185-189.
95. Matsubara S, Tanaka T, Tomari S, Fukuma K, Ishiyama H, Abe S, et al. Statin treatment can reduce incidence of early seizure in acute ischemic stroke: a propensity score analysis. Sci Rep. (2020) 10:1968.
96. Ifergan I, Wosik K, Cayrol R, et al. Statins reduce human blood-brain barrier permeability and restrict leukocyte migration: relevance to multiple sclerosis. Ann Neurol. 2006;60(1):45-55.
97. Moezi L, Shafaroodi H, Hassanipour M, Fakhrzad A, Hassanpour S, Dehpour AR. Chronic administration of atorvastatin induced anti-convulsant effects in mice: the role of nitric oxide. Epilepsy Behav. 2012;23(4):399-404.
98. Bösel J, Gandor F, Harms C, et al. Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones. J Neurochem. 2005;92(6):1386-1398.
99. van der Most PJ, Dolga AM, Nijholt IM, Luiten PG, Eisel UL. Statins: mechanisms of neuroprotection. Prog Neurobiol. 2009;88(1):64-75.
100. Tanaka T, Yamagami H, Ihara M, et al. Seizure Outcomes and Predictors of Recurrent Post-Stroke Seizure: A Retrospective Observational Cohort Study. PLoS One. 2015;10(8):e0136200.
101. Ahangar AA, Hosseini S, Saghebi R. Clinical features of post stroke seizure in Babol, northern Iran. Neurosciences (Riyadh). 2008;13(1):88-90.
102. Alvarez-Sabín J, Montaner J, Padró L, et al. Gabapentin in late-onset poststroke seizures. Neurology. 2002;59(12):1991-1993.
103. Oros MM, Smolanka VI, Sofilkanich NV, Borovik OI, Luts VV, Andrukh PG. Epilepsy after ishemic stroke: is it worth administering anticonvulsants after the first attack?. Wiad Lek. 2018;71(2 pt 1):269-272.
104. Silverman IE, Restrepo L, Mathews GC. Poststroke seizures. Arch Neurol. 2002;59(2):195-201.
105. Inoue Y, Nakamura F, Nishida T. Treatment guidelines for adult epilepsy. Rinsho Shinkeigaku. 2004;44(11):861–864.
106. Okuda S, Takano S, Ueno M, Hamaguchi H, Kanda F. Clinical features of late-onset poststroke seizures. J Stroke Cerebrovasc Dis. 2012;21(7):583-586.
107. Gilad R, Sadeh M, Rapoport A, Dabby R, Boaz M, Lampl Y. Monotherapy of lamotrigine versus carbamazepine in patients with poststroke seizure. Clin Neuropharmacol. 2007;30(4):189-195.
108. Consoli D, Bosco D, Postorino P, et al. Levetiracetam versus carbamazepine in patients with late poststroke seizures: a multicenter prospective randomized open-label study (EpIC Project). Cerebrovasc Dis. 2012;34(4):282-289.
109. Billinghurst LL, Beslow LA, Abend NS, et al. Incidence and predictors of epilepsy after pediatric arterial ischemic stroke. Neurology. 2017;88(7): 630-637.
110. Stephen LJ, Kwan P, Brodie MJ. Does the cause of localisation-related epilepsy influence the response to antiepileptic drug treatment?. Epilepsia. 2001;42(3):357-362.