Drugs & Aging (2021) 38:285–299 https://doi.org/10.1007/s40266-021-00837-7 REVIEW ARTICLE Seizures and Epilepsy After Stroke: Epidemiology, Biomarkers and Management Marian Galovic1,2,3 · Carolina Ferreira‑Atuesta2,3,4 · Laura Abraira5,6 · Nico Döhler7 · Lucia Sinka1 · Francesco Brigo8 · Carla Bentes9 · Johan Zelano10,11 · Matthias J. Koepp2,3 Accepted: 23 January 2021 / Published online: 23 February 2021 © The Author(s) 2021 Abstract Stroke is the leading cause of seizures and epilepsy in older adults. Patients who have larger and more severe strokes involving the cortex, are younger, and have acute symptomatic seizures and intracerebral haemorrhage are at highest risk of developing post-stroke epilepsy. Prognostic models, including the SeLECT and CAVE scores, help gauge the risk of epileptogenesis. Early electroencephalogram and blood-based biomarkers can provide information additional to the clinical risk factors of post-stroke epilepsy. The management of acute versus remote symptomatic seizures after stroke is markedly different. The choice of an ideal antiseizure medication should not only rely on efficacy but also consider adverse effects, altered pharma- codynamics in older adults, and the influence on the underlying vascular co-morbidity. Drug–drug interactions, particularly those between antiseizure medications and anticoagulants or antiplatelets, also influence treatment decisions. In this review, we describe the epidemiology, risk factors, biomarkers, and management of seizures after an ischaemic or haemorrhagic stroke. We discuss the special considerations required for the treatment of post-stroke epilepsy due to the age, co-morbidities, co-medication, and vulnerability of stroke survivors. 7 * Marian Galovic Specialist Clinic for Neurorehabilitation, Kliniken Beelitz, marian.galovic@usz.ch Beelitz‑Heilstätten, Germany 8 1 Division of Neurology, “Franz Tappeiner” Hospital, Merano, Department of Neurology, Clinical Neuroscience Italy Center, University Hospital and University of Zurich, 9 Frauenklinikstrasse 26, 8091 Zurich, Switzerland Department of Neurosciences and Mental Health 2 (Neurology), Hospital de Santa Maria-CHLN, Lisboa, Department of Clinical and Experimental Epilepsy, UCL Portugal Queen Square Institute of Neurology, London, UK 10 3 Department of Clinical Neuroscience, Institute Chalfont Centre for Epilepsy, Chalfont St Peter, UK of Neuroscience and Physiology, Sahlgrenska Academy 4 Department of Neurology, Icahn School of Medicine at University of Gothenburg, Gothenburg, Sweden at Mount Sinai, New York, USA 11 Department of Neurology, Sahlgrenska University Hospital, 5 Epilepsy Unit, Department of Neurology, Vall d’Hebron Gothenburg, Sweden Hospital Universitari, Barcelona, Spain 6 Universitat Autonoma de Barcelona, Bellaterra, Spain Vol.:(0123456789) 286 M. Galovic et al. 2 Epidemiology Key Points The majority of strokes occur in adults aged > 45 years Clinical characteristics, imaging and electroencephalo- [11]. Up to 90% of strokes are ischaemic, the remainder gram findings, and blood biomarkers may be integrated being haemorrhagic. Stroke is the most common identifi- into prognostic models to gauge the risk of seizures able aetiology of acquired epilepsy in high-income coun- following stroke. tries [12]. The treatment of post-stroke epilepsy needs to be Risk estimates of epilepsy after stroke have been exten- adapted to the individual, considering changes in phar- sively studied and vary with study methodology. In the macodynamics due to older age, co-morbidities, and general population, prospective follow-ups of large cohorts co-medications in stroke survivors. or register-based studies provide the most representative estimates. An incidence of post-stroke epilepsy of 6.4% Because older adults may be more prone to adverse was found both in a population-based study in London effects from antiseizure medications, their reduction or (UK) and in a nationwide registry in Sweden [13, 14]. complete withdrawal should be considered in seizure- In single-centre studies from academic hospitals, which free individuals. typically treat younger patients and more severe cases of stroke, the cumulative incidence of subsequent epilepsy can be above 15%, particularly in severely affected patients who receive thrombolysis [15, 16]. The incidence of epi- lepsy after haemorrhagic stroke is just above 12%. The risk of post-stroke epilepsy is greatest within the first years after stroke. In those who develop epilepsy, almost 85% 1 Introduction experience the first remote symptomatic seizure within the first 2 years after stroke [17]. Stroke is the most common cause of seizures and epilepsy The epidemiology of acute symptomatic seizures is less in older adults [1]. Post-stroke epilepsy eventually devel- well defined. Acute seizures were observed in 1–4% of ops in about 6% of the 3–6 million people who have a patients with ischaemic stroke but in up to 16% of those stroke annually [2]. Seizures shortly after stroke can lead with intracerebral haemorrhage [18, 19]. to increased metabolic stress and cell death, causing an increase in infarct size, mortality, and negative functional outcomes [3–5]. Recurrent seizures may lead to injuries, affect cognition and the ability to work or operate vehi- 3 Risk Factors, Imaging, and Prognostic cles, and decrease the quality of life [6, 7]. Older age, co- Models morbidities, co-medications, and the general vulnerability of stroke survivors must be taken into account in decisions Consistently identified risk factors of post-stroke epilepsy about when and how to treat post-stroke seizures. Here, include acute symptomatic seizures, cortical involvement, we review the epidemiology, risk factors, biomarkers, and stroke severity and aetiology, young age, and stroke type management of seizures after an ischaemic or haemor- (haemorrhagic vs. ischaemic) [13, 16, 19]. Similarly, a rhagic stroke. meta-analysis found acute symptomatic seizures, cortical Seizures after stroke are dichotomized into acute and involvement, and haemorrhage to increase the risk of epi- remote symptomatic. Acute symptomatic seizures (also lepsy after stroke. called ‘early’ seizures) occur within 7 days after an infarct The evidence for co-morbidities influencing the risk of [8] and are considered to be provoked by the toxic or meta- seizures after stroke is less consistent. Some results sup- bolic effects of stroke. Remote symptomatic seizures (also port an increased risk of vascular epilepsy in those with called ‘late’ seizures) are unprovoked seizures that occur diabetes, dyslipidemic, hypertension, peripheral infec- more than 1 week after stroke. The risk of subsequent tions, depression, or dementia [20]. unprovoked seizures after acute symptomatic seizures is The relationship between reperfusion therapies after about 30%, so acute symptomatic seizures are not consid- acute ischaemic stroke and acute and remote sympto- ered epilepsy as such because of this low risk of recur- matic seizures is currently unclear [21]. Several studies rence [9, 10]. In contrast, a single remote symptomatic suggested a higher risk of seizures in those receiving rep- seizure after stroke carries a > 60% risk of subsequent erfusion treatment [22, 23], whereas others did not find an unprovoked seizures and is sufficient for the diagnosis of association [24, 25]. There is a potential of confounding epilepsy in this context. Seizures and Epilepsy After Stroke 287 by treatment selection in these studies, because those with • Seizures are uncommon if the stroke affects only infraten- more severe strokes due to large vessel occlusion are more torial structures. likely to receive reperfusion treatment and have a higher • Larger lesions are more likely to cause seizures [30]: a risk of seizures. lesion size ≥ 70 ml increases the odds of seizures by Little is known on imaging biomarkers of epileptogen- fourfold [31]. esis, i.e. the development of epilepsy, after stroke [26]. No specific technique has so far proven helpful in visualizing Many of these risk factors are routinely available and can epileptogenesis in humans. Some clues on the risk of post- be combined to predict an individual’s overall risk of devel- stroke epilepsy can be obtained from magnetic resonance oping epilepsy after stroke. A prognostic model, termed imaging or computed tomography (CT) scans: SeLECT (Fig. 1), has been shown to accurately and reli- ably predict the risk of post-stroke epilepsy after ischaemic • Involvement of the cortex is highly associated with later stroke [19]. It involves five parameters: Severity of stroke, seizures. Large-artery atherosclerotic aetiology, Early seizures, Cor- • Subcortical stroke does not increase the risk of post- tical involvement, and Territory of middle cerebral artery stroke epilepsy [27]. involvement. The highest SeLECT score (9 points) indicates • Seizures are most common if the infarct or bleeding a more than 80% risk of epilepsy within 5 years after stroke affects the anterior circulation [28] and, more specifi- (Fig. 1). The model is available as the ‘SeLECT score’ app cally, the medial cerebral artery territory [29]. on the Apple AppStore and Google Play Store. Fig. 1  Prediction of remote symptomatic seizures after ischaemic seizures according to different SeLECT values. The risk of remote stroke using the SeLECT score. a Calculation of the SeLECT score; symptomatic seizures after c 1 year and d 5 years. Reproduced from b Kaplan–Meier estimate curves of the risk of remote symptomatic Galovic et al. [19] with permission 288 M. Galovic et al. Fig. 2  Prediction of remote symptomatic seizures after intracerebral haemorrhage using the CAVE score. a Calculation of the CAVE score; b risk of remote symptomatic seizures according to CAVE score dur- ing follow-up in the derivation and validation cohorts. For details see Sect. 3 The CAVE score (Fig. 2) has been developed to gauge 4 Electroencephalogram After Stroke seizure risk after intracerebral haemorrhage and includes the factors Cortical location, younger Age, large hema- The electroencephalogram (EEG) has a high temporal reso- toma Volume, and acute symptomatic sEizure [32]. The lution, is important for the evaluation of brain function in highest CAVE score (4 points) indicates a 46% risk of real time, and is the gold standard for identifying differ- later seizures. ent epileptogenesis and ictogenesis biomarkers [35, 36]. A These scores are helpful in stratifying stroke survivors systematic review and meta-analysis [37] found ictal and into low- and high-risk categories for the development of interictal epileptiform activity on EEG after stroke in 7% post-stroke epilepsy and to guide targeted follow-up. No (95% confidence interval [CI] 3–12) and 8% (95% CI 4–13) treatment has so far proven beneficial for primary preven- of patients, respectively. These values may be even higher tion of post-stroke epilepsy. Although these scores are not if long-term EEG monitoring is installed. an instrument to guide primary preventive treatment, they In an intensive care unit environment, seizures are fre- may be used as recruitment tools for prospective studies of quently ‘nonconvulsive’ and may not be detected by clinical antiepileptogenic drugs. observation. EEG monitoring in this setting is essential for In animal models of acquired epilepsy, a number of the diagnosis and treatment of seizures and status epilepti- medications in clinical use for diverse indications have been cus [38–40]. Among patients with acute stroke receiving reported to have an antiepileptogenic effect [33], including EEG monitoring, epileptic activity can be detected in 17% the antiseizure medications (ASMs) levetiracetam, brivar- of cases [41]. In ischaemic stroke, 11% had seizures [42, 43], acetam, eslicarbazepine, topiramate, gabapentin, pregaba- 9% had exclusively nonconvulsive seizures, and 7% fulfilled lin, and vigabatrin. With the exception of levetiracetam for criteria for nonconvulsive status epilepticus [44]. Noncon- post-traumatic epilepsy, none of these medications have vulsive status epilepticus is associated with poor outcomes been studied systematically with the view of translation and increased mortality [45]. A prospective study found non- into clinical studies. This has contributed to the fact that convulsive status epilepticus in 4% of patients with acute almost none of the preclinical projects have led to clinical ischaemic stroke [46]. Clinicians did not suspect ongoing translation [34]. One main reason for the lack of anti-epilep- epileptic activity in 40% of the cases with nonconvulsive togenesis trials is the relatively low (6%) risk of post-stroke status epilepticus on EEG. Thus, prolonged EEG monitoring epilepsy in unselected stroke cohorts, which would require may help detect status epilepticus even in patients without large numbers of patients (N = 1500) to show a moderate typical clinical signs of ongoing seizures. treatment effect (50% reduction) during a reasonable obser- Limited data exist on the role of EEG in a stroke unit vation period (18–24 months) following stroke. Tools such setting. More than one-fifth of patients with seizures in a as the SeLECT score are required to provide an enriched stroke unit had exclusively electrographic seizures [47]. A population with at least a 20% risk of remote seizures fol- short-duration EEG identified 22.7% of acute symptomatic lowing stroke to allow for an antiepileptogenesis trial to be seizures in patients with an anterior circulation ischaemic feasible (N = 400). stroke that were exclusively electrographic and therefore Seizures and Epilepsy After Stroke 289 could not otherwise be recognized. Follow-up EEG may a higher synaptic plasticity in those with acute symptomatic also help identify epilepsia partialis continua, which was seizures [57]. TNF-R1 is a proinflammatory cytokine that observed in 1.7% of patients 1 year after the stroke [48]. may exhibit a proconvulsive effect [58]. Lower levels of The role of an early EEG in the prediction of post-stroke TNF-R1 in the blood of patients with acute symptomatic sei- epilepsy is a pertinent clinical question but remains poorly zures could point towards increased binding of these recep- explored. One prospective study [49] established early post- tors to TNFα during stroke-induced neuroinflammation. stroke visual EEG features as independent predictors of epi- Post-stroke epilepsy (Fig. 4b) was associated with lower lepsy 1 year after stroke. The main risk factor on EEG was levels of S100 calcium-binding protein B (S100B) and the early presence of interictal epileptiform activity (Fig. 3). heat shock 70 kDa protein-8 (Hsc70) and higher levels of The authors also proposed that the presence of periodic dis- endostatin in the blood within 6 h of stroke onset [59]. The charges in an early EEG after stroke and the presence of incidence of post-stroke epilepsy was 17% in cases with islands of preserved cortex within the infarct in the CT scan abnormalities in all three biomarkers, compared with less could help to identify patients requiring a more extensive or than 1% in those with no biomarker abnormalities. Another repetitive neurophysiological assessment in the stroke unit. group observed increased levels of blood biomarkers of Early EEG may also help in the differential diagnosis brain injury (S100B, neurofilament light, tau, glial fibrillary between an epileptic seizure and a transient ischaemic attack acidic protein, and neuron-specific enolase) in four subjects [50], particularly if imaging does not show an infarct. An with post-stroke epilepsy [60]. S100B and Hsc70 belong EEG may support the clinical diagnosis of seizure in less to the DAMPs family of proteins that are released during than half of suspected cases [51]. Patients with seizures may the neuroinflammatory phase after a stroke [33]. Reduced show specific or nonspecific EEG abnormalities, whereas levels of these proteins in those who later develop epilepsy 90% of patients with transient ischaemic attack had a normal may seem counter-intuitive, but S100B and Hsc70 are rel- EEG [52]. evant for maintaining the functional integrity of the BBB, and reduced levels could aggravate BBB deficiency [61]. Endostatin is an inhibitor of angiogenesis and contributes 5 Blood and Genetic Biomarkers to mediating neurogenesis and cellular proliferation [62]. A transient angiogenic response is observed after brain dam- A biomarker is defined as an objectively measured char- age; thus, upregulation of endostatin could compromise cel- acteristic of a normal or pathologic biologic process [35]. lular repair. Biomarkers of epileptogenesis may help predict the develop- The fact that different biomarkers were observed in ment of epilepsy following stroke. patients with acute and remote symptomatic seizures sup- Stroke-induced acute neuronal damage (hypoxia, meta- ports the notion that diverging mechanisms underlie these bolic dysfunction, global hypoperfusion, glutamate excito- seizure types [12, 13]. In both cases, blood biomarkers may toxicity, ion channel dysfunction, and blood–brain barrier improve the prediction of patients who later experience [BBB] disruption) triggers a neuroinflammatory cascade. acute or remote symptomatic seizures and could be valu- Consequently, multiple inflammatory mediators are released able in addition to clinical or imaging factors. to repair the brain damage (damage-associated molecular Little is known about genetic factors and their role in patterns [DAMPs], cytokines, chemokines, complement, post-stroke epilepsy. There may be a familial predisposition prostaglandins, and growth factors). When neuroinflamma- towards the development of vascular epilepsy, as suggested tion persists over time, it can lead to neuronal and astroglial by the higher risk of post-stroke seizures in those with a dysfunction and, consequently, altered synaptic transmis- first-degree relative with epilepsy, but the risk increase was sion, hyperexcitability, neuronal loss, gliosis, and aberrant small [63]. Three studies have assessed the contribution of neurogenesis. Hence, all these mechanisms may be involved genetic variants to epileptogenesis in patients with stroke in the process of epileptogenesis [33, 53]. [64–66]. Yang et al. [64] reported that allele A of the rs671 Some of the inflammatory molecules that are released polymorphism in a gene encoding mitochondrial aldehyde after a brain insult have been evaluated as biomarkers in dehydrogenase 2 was associated with post-stroke epilepsy several stroke complications such as haemorrhagic transfor- and increased the plasma concentration of aldehyde dehy- mation or pneumonia [54, 55]. However, the role of these drogenase 2 substrate, 4-hydrozynomenal. Zhang and col- biomarkers in predicting post-stroke epilepsy is uncertain. leagues reported that a cluster of differentiation (CD)-40- Acute symptomatic seizures (Fig. 4a) were associated 1C/T polymorphism might be associated with post-stroke with higher neural cell adhesion molecule (NCAM) and epilepsy. They suggested increased plasma concentrations lower tumour necrosis factor receptor 1 (TNF-R1) levels of sCD40L that are involved in the inflammatory response in blood during the first 6 h after stroke onset [56]. NCAM as a potential mechanism [65]. Fu et al. [66] reported that a may play a role in cellular adhesion and could point towards polymorphism of TRPM6 (rs2274924) might be associated 290 M. Galovic et al. Fig. 3  Epileptiform electroencephalogram (EEG) findings in stroke localization on the right in a patient with acute right-hemispheric survivors. a EEG in a patient with acute right-hemispheric stroke stroke affecting the middle cerebral artery territory. Findings on affecting the middle cerebral artery territory. Findings on source source montage include slow wave activity over the right anterior and montage include focal slow wave activity over the right medial tem- medial temporal regions (F8 and T4 electrodes) and right temporal poral region (T4 electrode) and epileptiform activity (a spike wave (T4 electrode) epileptiform activity (sharp wave marked with a black marked with a black arrow). b EEG and corresponding spike source square) with corresponding source localization on the right Seizures and Epilepsy After Stroke 291 Fig. 4  Blood biomarkers of acute and remote symptomatic seizures 6 interleukin 6, NCAM neural cell adhesion molecule, NT-proBNP after stroke. Radar charts of z-scores for biomarkers of a acute or b N-terminal Pro-B-type natriuretic peptide, S100B S100 calcium-bind- remote symptomatic seizures. ApoCIII apolipoprotein CIII, FasL Fas ing protein B, TNF tumour necrosis factor, VAP-1 vascular adhesion ligand, GroA growth-related oncogene α, Hsc70 heat shock 70 kDa protein-1, vWF von Willebrand factor. Reproduced from Abraira and protein-8, IGFBP-3 insulin-like growth factor binding protein-3, IL- colleagues [56, 59] with permission with susceptibility to epilepsy following ischaemic stroke. practice. Off-label administration of ASM is frequently ini- In addition, post-stroke epilepsy patients with this polymor- tiated after an acute symptomatic seizure. Such treatment phism had significantly decreased serum levels of ­Mg2+, is usually time limited and restricted to several weeks or indicating that TRPM6 polymorphism may also influence months after the stroke. Many clinicians pursue such an serum levels of ­Mg2+ in these patients [66]. approach aiming to avoid further seizures and prevent their potential negative impact on clinical outcomes [70]. Ade- quately powered controlled trials for the prevention or even 6 Management of Acute Symptomatic treatment of acute symptomatic seizures are not available. Seizures Despite the relatively low risk of recurrences after acute symptomatic seizures, such seizures may not be entirely The temporal cut-off for acute (≤ 7 days) versus remote (> 7 benign. Ictal patterns and periodic discharges on EEG days) symptomatic seizures after stroke has been set, hypoth- are associated with neurological deterioration after stroke esizing fundamentally different aetiologic mechanisms. [5]. Seizures and periodic discharges are associated with Early seizures are assumed to be caused by potentially tran- increased metabolic demand [71] and can lead to metabolic sient processes in the acute phase after stroke, including crisis [72]. Thus, treatment of early seizures or epileptic hypoxia, cerebral perfusion shift, neuronal metabolic dys- activity on EEG may be relevant in situations with reduced function, and excitotoxicity as well as BBB disruption [67]. brain perfusion. These include ischaemic stroke with hemo- Although they occur infrequently, they have been associated dynamically relevant stenosis, brain oedema, or vasospasms with elevated mortality [10, 68] and are a risk factor for the after subarachnoid haemorrhage. Other relevant conditions development of epilepsy [19, 69]. Patients with acute symp- include recent surgery or trauma, where repeated acute tomatic seizures after stroke have a 10-year recurrence risk symptomatic seizures could lead to worsening. In these situ- for unprovoked seizures of 33% [9, 10]. Thus, acute sympto- ations, short-term treatment with ASM may be warranted. matic seizures alone are insufficient to diagnose epilepsy. In In most other cases, treatment of isolated acute symptomatic contrast, remote symptomatic seizures have a recurrence rate seizures is neither necessary nor recommended [70, 73]. of 72% within 10 years; because of this high recurrence risk, Another aspect of early treatment is the potential to inter- a single remote unprovoked seizure qualifies as epilepsy [9]. fere with epileptogenesis. There is little evidence to support Overall, the management of acute symptomatic seizures such primary preventive treatment. ASMs suppress seizures after stroke is much debated. Given the low recurrence risk but do not have documented effects on antiepileptogenesis. of acute symptomatic seizures, the initiation of ASMs is Currently available prognostic models and biomarkers usually not recommended. However, there is a discrepancy do not allow prediction of the later development of post- between guideline recommendations and common bedside stroke epilepsy with sufficient certainty to warrant primary 292 M. Galovic et al. preventive treatment. Although experimental findings for is mainly guided by the patients’ age, co-morbidities, and antiepileptogenic treatment have been promising [74], they co-medications. have not been replicated in humans [73]. The evidence supporting the use of specific ASMs is lim- Antiepileptogenic treatment trials mostly focused on pri- ited and of low quality [83, 84]. Two randomised open-label mary prevention of epilepsy after traumatic brain injury or studies compared controlled-release carbamazepine and brain tumours, and the results were negative [75]. One ran- lamotrigine [85] or levetiracetam [86]. These studies were domized controlled trial evaluating the primary prevention conducted in a small number of patients so were underpow- of post-stroke epilepsy with levetiracetam compared with ered to reveal a statistically significant and clinically relevant placebo did not include a sufficient number of participants difference between the drugs in 12-month seizure-freedom to allow any definitive conclusions [76]. rates (44 and 85% for controlled-release carbamazepine; Some recent interest surrounded the use of eslicarbaz- 72 and 94% for lamotrigine and levetiracetam). However, epine acetate [77] and sodium selenate [78] as potentially in both studies, controlled-release carbamazepine was less antiepileptogenic compounds. Several observational studies well-tolerated than lamotrigine and levetiracetam, a find- found a reduced incidence of acute symptomatic seizures ing consistent with other studies conducted in older adults in patients who were prescribed statins [17, 79]. One study with epilepsy of various aetiologies. Both these studies were also found a lower risk of epilepsy within 1 year after stroke open label and of low quality with an unclear or high risk in patients started on simvastatin [80]. Such observational of selection bias, allocation concealment, performance bias, analyses are limited by potential confounding or treatment and detection bias [84]. A recent systematic review with selection bias, and the results should be interpreted with cau- network meta-analysis of these two trials showed no dif- tion. These observations will need to be replicated in larger ference between levetiracetam and lamotrigine for seizure prospective controlled trials. freedom (odds ratio [OR] 0.86; 95% confidence interval [CI] 0.15–4.89), potentially due to a lack of statistical power to detect a difference [84]. However, it showed a greater occur- rence of adverse events for levetiracetam than lamotrigine 7 Management of Post‑Stroke Epilepsy (OR 6.87; 95% CI 1.15–41.1) [84]. Uncontrolled trials showing the efficacy and tolerabil- The use of ASMs aims to reduce the risk of seizure recur- ity of individual drugs such as eslicarbazepine acetate [87], rence. Typically, they are reserved for the treatment of gabapentin [88], levetiracetam [89, 90], valproic acid, and unprovoked remote symptomatic seizures, which, unlike other newer ASMs [91] are also sparse. However, the valid- acute symptomatic seizures, have a high risk of recurrence. ity of these studies is limited by bias, placebo effect, regres- However, the choice of starting an ASM treatment after a sion to the mean, and other confounding factors. single unprovoked post-stroke seizure should always rely Given the lack of high-quality evidence to support the on an overall assessment of the patient. In some cases, there use of specific ASM for the treatment of post-stroke sei- may be reasons to justify deferral of treatment or no treat- zures, drug selection should rely mostly on the results of ment at all, for instance, in patients under constant super- randomised controlled trials conducted in older adults with vision, lack of ambulation with low risk of seizure-related focal epilepsy of various aetiologies. These studies have injury, and very mild seizures [14]. evaluated the efficacy and tolerability of gabapentin [92], If prophylactic treatment after a first unprovoked seizure lacosamide [93], lamotrigine [92, 94–96], levetiracetam is appropriate or necessary, the selection of ASM should [97], and valproic acid [97] tested against immediate- or rely on the best evidence available in the literature and controlled-release carbamazepine. They consistently showed consider some clinical and pharmacological issues [73]. A that newer ASMs had a better tolerability profile than car- pragmatic approach is to ‘start slow and aim low’. This will bamazepine, without significant differences in seizure reduce the intensity and risk of adverse effects and establish control and sometimes with higher retention rates [94, 96, a therapeutic response at the lowest viable dose [81]. Many 97]. Recently, a network meta-analysis estimated the com- patients with post-stroke epilepsy respond well to even low- parative efficacy and safety of ASMs in older adults with dose treatment [82]. Monotherapy is usually preferred to new-onset epilepsy [98]. No significant difference in effi- polytherapy. Dose finding needs to consider kidney and liver cacy was found across treatments, although lacosamide, function and body weight. The use of soluble medications lamotrigine, and levetiracetam had the highest probability may be helpful in stroke survivors with dysphagia. Most of ranking best for achieving seizure freedom, whereas studies evaluated ASMs in ischaemic stroke, and only little immediate- and controlled-release carbamazepine showed data exist on ASM usage in primary haemorrhagic stroke. a less favourable tolerability profile, with higher withdrawal Nevertheless, the principles of treatment in ischaemic and rates than levetiracetam and valproic acid [98]. However, haemorrhagic stroke are similar, and treatment selection results from trials conducted in older adults, particularly Seizures and Epilepsy After Stroke 293 those on efficacy, should be generalised with caution to the far only sporadic case reports in humans exist [105, 106]. population of patients with post-stroke epilepsy because of Thus, further clinical studies are required to evaluate the the differences in the proportion of patients with post-stroke clinical relevance of these drug interactions. Until then, epilepsy included in each trial. A recent exploratory post hoc caution should be taken when using certain ASMs with analysis of comparative trials between lacosamide and con- novel oral anticoagulants. trolled-release carbamazepine showed that lacosamide was Pharmacodynamics may be altered in older adults. Renal generally well-tolerated in patients with post-stroke epilepsy function declines steadily with increasing age. Potential [99]. More patients on lacosamide than controlled-release exists for reduced hepatic metabolism, protein binding, and carbamazepine completed 6 months (82 vs. 59%) and 12 enzyme induction. The effect of ageing on pharmacody- months (67 vs. 50%) of treatment without seizure at the last namics and changes in homeostatic mechanisms and neu- evaluated dose, whereas no formal statistical analysis was rotransmission can increase the risk of adverse effects in possible [99]. Lacosamide was also reported as a safe poten- this population [107]. Older adults are more vulnerable to tial treatment of nonconvulsive status epilepticus in older dose-related adverse effects, typically including drowsiness, adults, but prospective comparative trials will be necessary fatigue, dizziness, blurry vision, impaired concentration or to determine its efficacy [100]. memory, and ataxia [108]. Cognitive decline is more common in older adults. The sedative and anticholinergic burden of ASMs, particularly 8 Adverse Effects and Interactions those given as polytherapy, may aggravate cognition [109]. Negative impacts on cognition were particularly observed Drug selection in older adults should not only rely on drug with ‘older’ ASMs, i.e. those developed before 1990, and efficacy but also individually consider appropriate dosing were documented for phenobarbital, carbamazepine, phe- in the light of changing pharmacodynamics as well as the nytoin, and valproate [110]. The most prominent effects increased potential for adverse effects and interactions. By on cognition were seen with phenobarbital. Of the ‘newer’ definition, all patients with post-stroke seizures have vascu- ASMs, dosage-dependent cognitive impairment affecting lar co-morbidity, take other drugs (e.g. antiplatelet agents or verbal function is an adverse effect of topiramate, particu- anticoagulants, statins, anti-hypertensive drugs, etc.), and are larly in dosages higher than 75 mg/day [111]. Other newer likely to be aged ≥ 65 years and have residual neurological ‘ASMs’, such as gabapentin, lamotrigine, and levetiracetam, deficits [101]. Hence, the ideal ASM should have minimal showed fewer adverse cognitive effects than carbamazepine or no detrimental effect on the underlying vascular disease, [112, 113]. for instance, it should not affect surrogate markers associ- Psychiatric and behavioural adverse effects are particu- ated with increased risk of cardio/cerebrovascular accidents larly relevant in those with a history of psychiatric condi- (e.g. low-density cholesterol, lipoprotein, C-reactive protein, tions, intractable seizures, secondarily generalized seizures, homocysteine, carotid artery intima-media thickness, etc.) and absence seizures [114]. Levetiracetam (22%) and zon- [102, 103]. Furthermore, it should have no relevant drug isamide (10%) were particularly likely to induce behavioural interactions, be effective, well-tolerated, and safe to admin- adverse effects. By contrast, carbamazepine, oxcarbazepine, ister in patients with renal or hepatic failure. gabapentin, lamotrigine, phenytoin, clobazam, and valproate Accordingly, enzyme-inducing ASMs, such as car- were associated with better behavioural tolerability [115, bamazepine, phenytoin, phenobarbital, and primidone, 116]. Drug–drug interactions can also lead to a reduction should be avoided whenever possible, as they can increase of the plasma level of concurrent psychotropic medicines, serum levels of lipids and other biochemical markers of resulting in a decline in the efficacy of antidepressant medi- vascular disease [101]. Furthermore, they can increase cation [117]. the hepatic metabolism of several co-medications, some Bone health is a relevant issue in older adults. Enzyme- of which (e.g. warfarin) are used in post-stroke patients. inducing ASMs, such as phenobarbital, phenytoin, carba- Recently, the European Heart Rhythm Association advised mazepine, and primidone, as well as the enzyme inhibi- against the use of some ASMs in association with non- tor valproate, may increase the risk of fractures. Enzyme vitamin K antagonist oral anticoagulants [104] because induction can lead to accelerated metabolism of vitamin D of the potential risk of decreasing the anticoagulant and increased bone turnover [118–120]. In the case of val- effect by inducing P-glycoprotein (carbamazepine, leveti- proate, its bone-depleting properties result from the inter- racetam, phenobarbital, phenytoin, and valproic acid) or ference with the function of osteoblasts [121]. The duration cytochrome P450 3A4 activity (carbamazepine, oxcarbaz- of the ASM therapy is an important factor for the decrease epine, phenytoin, phenobarbital, and topiramate) [105]. of bone density and the risk of fractures. Particular caution However, these recommendations are based on the sum- is required when using these ASMs in older women with a mary of product characteristics and expert opinions, as so history of osteoporosis [122]. 294 M. Galovic et al. Hyponatraemia may commonly occur through pharmaco- seizure freedom may reduce the risk of relapses compared dynamic interactions when carbamazepine, oxcarbazepine, with earlier withdrawal [133, 134]. Given that more than or eslicarbazepine acetate are prescribed to patients treated two-thirds of individuals with post-stroke epilepsy achieve with thiazides or other diuretic drugs [123, 124]. Oxcarbaz- seizure freedom with one ASM, which is similar to other epine has the highest propensity to cause hyponatraemia. epilepsy aetiologies [135], some of these individuals may Although hyponatraemia is commonly mild and develops benefit from medication withdrawal. slowly, it may aggravate seizure control and cause confusion A recent study developed a prognostic model to guide or delirium in stroke survivors. ASM withdrawal in seizure-free individuals, but the model is not specific to post-stroke epilepsy (Fig. 5) [133]. Factors that predict good outcomes include a shorter duration of 9 Withdrawal of Antiseizure Medication epilepsy before remission, longer seizure-free interval before withdrawal, younger age of epilepsy onset, no history of Whether ASMs should be continued should be evaluated febrile seizures, self-limited epilepsy syndromes, no devel- regularly. Withdrawal of medication is an option, particu- opmental delay, and normal EEG before withdrawal [133]. larly in those with long periods of seizure freedom or with This model does not include imaging abnormalities and has very mild and infrequent seizures. Older adults may benefit not been tested specifically in stroke survivors. The presence from medication withdrawal as it may lessen adverse effects of a lesion after an ischaemic infarct or intracerebral haem- [85, 86] and prevent interactions with anticoagulants [125], orrhage likely reduces the chances of remaining seizure free lipid-lowering drugs [126, 127], or other drugs commonly after complete withdrawal of medication. Hence, ASM with- prescribed for older adults [126, 128]. Furthermore, ASM drawal in stroke survivors needs to be performed cautiously therapy may negatively impact motor recovery [129] and using an individually tailored approach because seizure bone density and increase healthcare costs [130], serum relapses may increase mortality risk [136] and deteriorate lipids, weight, and risk of cardiac arrhythmias [103]. Studies neurological function [137]. Further studies are needed to evaluating the risk of relapse after ASM withdrawal in peo- address the risk of relapses after ASM withdrawal in post- ple with lesional epilepsy have shown an increased risk for stroke epilepsy. seizure relapses when withdrawal is attempted [131, 132]. For individuals who started ASM therapy after acute The decision to begin withdrawal should be individual- symptomatic seizures, the general advice is to withdraw ized based on a patient’s clinical characteristics, co-medica- medication early after stroke because acute symptomatic sei- tions, stroke type/morphology, co-morbidities, and personal zures have a low risk of recurrence [14, 73, 138, 139]. The preferences [73, 133]. Withdrawal after at least 2 years of optimal ‘observation period’ before early ASM withdrawal Fig. 5  Prediction of seizure recurrence after antiseizure medication withdrawal. Nomogram to predict seizure recurrence risk after 2 or 5 years following antiseizure medica- tion withdrawal. The nomogram is not specific to post-stroke epilepsy. Reproduced from Lamberink et al. [133] with permission Seizures and Epilepsy After Stroke 295 following acute symptomatic seizures is unknown, and clini- Ethics approval Not applicable. cal practice varies considerably. The authors of this article Consent to participate Not applicable. typically wait between 1 week and 3 months before initiat- ing ASM withdrawal if ASMs were started after an acute Consent for publication Not applicable. symptomatic seizure. From a pathophysiological perspec- tive, there is little reason to continue ASM treatment of acute Availability of data and material Not applicable. symptomatic seizures beyond the acute phase unless the risk Code availability Not applicable. of unprovoked remote symptomatic seizures is considered very high. An observational study concluded that individu- Author contributions All authors contributed sections to the first als receiving ASM immediately after the first post-stroke draft of the manuscript. MG combined the sections to a first draft. All authors revised the manuscript draft for intellectual content and read seizure had the same risk of relapse after withdrawal as those and approved the final version. who did not receive ASM during the first 2 years [139]. In addition, none of the current available ASMs have been Open Access This article is licensed under a Creative Commons Attri- shown to prevent epileptogenesis or to improve the long- bution-NonCommercial 4.0 International License, which permits any term prognosis [140] or mortality [141]. non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Com- mons licence, and indicate if changes were made. The images or other 10 Conclusions third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons There are several avenues for future research on post-stroke licence and your intended use is not permitted by statutory regula- epilepsy. Refinement and development of biomarkers of tion or exceeds the permitted use, you will need to obtain permission epileptogenesis will be important to predict which stroke directly from the copyright holder. To view a copy of this licence, visit survivors will later on have seizures. Such knowledge will http://creat​iveco​mmons​.org/licen​ses/by-nc/4.0/. also help recruitment for antiepileptogenic treatment trials. Stroke is an excellent model for such trials because the epi- leptogenic insult is usually well-defined and the latent period References between an infarct and the development of seizures provides time for interventions. 1. Lühdorf K, Jensen LK, Plesner AM. Etiology of seizures in the The effect, tolerability, and interactions of ASMs will elderly. 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