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Epilepsy after stroke: Definitions, problems and a practical approach for clinicians
NEUROL 1968 1–7 revue neurologique xxx (2018) xxx–xxx
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General review
Epilepsy after stroke: Definitions, problems and a practical approach for clinicians M. Quirins *, C. Dussaule, C. Denier, P. Masnou Service de neurologie adulte, CHU Biceˆtre, 78, avenue du Ge´ne´ral Leclerc, 94270 Le Kremlin Biceˆtre, France
info article
abstract
Article history:
Stroke, whether ischemic or hemorrhagic, is the main etiology of epilepsy in the elderly.
Received 23 January 2018
However, incidences and outcomes differ according to stroke subtype and delay of onset
Accepted 28 February 2018
following the stroke. While the medical literature is extensive, it is not always consistent,
Available online xxx
and many questions still remain regarding risk factors and management of vascular epilepsy. Thus, the present report here is an overview of the clinical aspects of vascular
Keywords:
epilepsy using a practical approach that integrates data from meta-analyses and the more
Stroke
recently published expert recommendations. # 2018 Elsevier Masson SAS. All rights reserved.
Seizure Early onset Late-onset seizure Vascular epilepsy
1.
Introduction
Stroke is the most common etiology for seizures and epilepsy in the elderly, representing nearly half of all symptomatic epilepsies in patients aged > 60 years [1–3]. Post-stroke seizures can manifest either soon after the onset of stroke or be delayed, and few definitions are necessary. First, ‘seizures at onset’ arise at the same time as stroke; ‘early seizures’ appear within 7 days according to a recent definition, but as they correspond to acute symptomatic seizures [4], there is no need to even mention epilepsy; and finally, ‘late-onset seizures’ or ‘unprovoked seizures’ manifest after 7 days. According to the latest revised classification of the International League Against Epilepsy (ILAE), a lateonset seizure in the context of stroke defines vascular epilepsy, making it no longer necessary to wait for a second seizure [5].
Distinguishing between these different types of seizures is not only a semantic problem, but also one based on different pathophysiological mechanisms. Early post-stroke seizures are associated with biochemical changes: cytotoxic neurotransmitters are released and induce neuronal hyperexcitability in the area of the penumbra by increasing extracellular glutamate, and intracellular sodium and calcium. In contrast, late-onset seizures have a pathophysiological mechanism similar to that of post-traumatic seizures, involving gliosis and hemosiderin deposits [1,6]. Considerable data are available on post-stroke seizures, but the results are somewhat variable, thereby requiring several caveats for interpretations and comparisons [7]: first, the definition of early seizures is variable: while usually between 7 and 14 days, it can nonetheless range from 2 days to 1 month [8]; second, early and late post-stroke seizures are not always distinguishable by stroke subtype (cerebral infarction, sub-
* Corresponding author. E-mail address: [email protected] (M. Quirins). https://doi.org/10.1016/j.neurol.2018.02.088 0035-3787/# 2018 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Quirins M, et al. Epilepsy after stroke: Problems and a practical approach for clinicians. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.02.088
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arachnoid or intracranial hemorrhage, cerebral venous thrombosis); and finally, from an electrophysiological point of view, until recently, it was almost never stated whether seizures had been defined clinically, electrically or by both. Furthermore, as there are no randomized controlled trials with sufficient power, any evidence to support recommendations is limited [9]. Thus, the present report is an overview of the clinical aspects of vascular epilepsy using a practical approach that integrates data from meta-analyses and more recently published recommendations (Fig. 1).
2.
Seizures at stroke onset
Seizures manifest at onset in 4.3–6.2% of ischemic strokes, and in 10.7–15.6% of hemorrhagic strokes [10–12]. The main risk factor for these seizures is hemorrhagic stroke, although female gender, younger age and less-severe motor deficit have also proved to be significant risk factors [13]. One study of prehospital diagnostic accuracy in stroke found that, in 76 cases of epileptic seizures, six strokes associated with seizure at onset went undiagnosed while, on the other hand, stroke was erroneously mentioned in 14 patients [14]. It is important to bear in mind the possibility of seizures at stroke onset so as
not to prematurely preclude eligible patients from receiving intravenous thrombolysis or mechanical thrombectomy. Previously, contraindications for tissue plasminogen activator (tPA) included epileptic seizures to avoid carrying out the procedure in cases of postictal deficit mimicking stroke. However, since then, magnetic resonance imaging (MRI) and perfusion sequences have been developed that allow more precise diagnoses to be made. It has also been shown that, in cases of seizures not associated with ischemia, tPA is a safe procedure [15,16]. Thus, to date, recommendations from various learned societies have been revised, and now specify that if the residual deficit can be attributed to ischemia and not only postictal deficit, then seizures are no longer a contraindication for intravenous thrombolysis [17,18].
3.
Early post-stroke seizures
3.1.
Epidemiology
The incidence of early post-stroke seizures is highly variable depending on differences in methodology, as discussed previously. Rates are, on average, between 2% and 4% of ischemic strokes [8], and between 10% to 16% of intracranial hemorrhages [17–19]. Around half of cases manifest within the
Fig. 1 – A practical summary of seizures after stroke. US: unprovoked seizure; LTG: lamotrigine; GBP: gabapentin; LEV: levetiracetam; LCS: lacosamide; ZNS: zonisamide; CBZ: carbamazepine; OCZ: oxcarbazepine. Please cite this article in press as: Quirins M, et al. Epilepsy after stroke: Problems and a practical approach for clinicians. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.02.088
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Other factors
Alcoholism Watershed infarcts Cardioembolism, multiple territory infarcts
No # No # # # # # Yes # # #
Hyperglycemia Hyponatremia
Yes # Yes # # # # # No # # # # No No Yes No No No Onset only No No No #
Young age Size/severity
# Yes Yes Yes No Yes No Onset only Yes Yes No #
I: ischemic stroke; H: intracerebral hemorrhage; SAH: subarachnoid hemorrhage; US: unprovoked seizure; #: not studied or not applicable. Intracerebral or hemorrhagic transformation of ischemic stroke.
Differential diagnoses
These include, in the first place, stroke recurrence, thereby requiring regular (control) brain imaging in case of emergencies. In the context of recent stroke, blood sugar disorders (hypo- or hyperglycemia) can induce changes on both neurological examination and seizures. In particular, metabolic disorders are purveyors of arousal fluctuations. It is also well known that toxic and metabolic encephalopathies can induce asterixis (distal negative myoclonus), which should not be confused with epileptic clonic seizures. In such cases, EEG recordings are essential for making the diagnosis and avoiding the unnecessary addition of an antiepileptic drug that can worsen encephalopathy. Two other less-well-known conditions responsible for differential diagnoses, but yet still not abnormal epileptic movements, are limb-shaking and midbrain strokes or acute insults of the subthalamic nuclei. Limb-shaking is clinically manifested by limb tremor mimicking myoclonia, but manifesting exclusively on standing (orthostatism). The pathophy-
a
3.3.2.
US only Yes # Yes Yes Yes Yes Yes Yes Yes Yes #
Clinical presentation
The clinical diagnosis of early seizures is sometimes easy, especially in cases of clonic manifestations on the side of hemiplegia. However, this situation is unusual, and the symptomatology is more often non-specific, with fluctuating arousal or transient worsening on neurological examination [2]. Thus, in these cases, diagnosis can be difficult and, in our experience, standard 20-min electroencephalography (EEG) is rarely contributory.
Cortical involvement
3.3.1.
Hemorrhagea
Diagnosis
Table 1 – Risk factors for acute symptomatic seizures: summary of some study results.
3.3.
Yes # Yes # No Yes Yes # Yes Yes # Yes
Early post-stroke seizures are mostly focal and with or without consciousness impairment [4,6]. Status epilepticus is uncommon, manifesting in only 0.14–1.1% of strokes, but may be the initial presentation in 0.12% of cases, representing 5–27% of this type of seizures [25–27]. On the other hand, 22% of new-onset status epilepticus cases are related to stroke. However, the influence of status epilepticus on the prognosis remains controversial: one study showed a twofold greater risk of mortality at 6 months [28], whereas another showed no increase in mortality [27]. It is also unclear whether early poststroke status epilepticus is a risk factor for late-onset seizures [27,29].
I, H, SAH I I H I, H, SAH I, H I, H H I, H I, H I I
Type of seizures
Stroke subtype
3.2.
Serafini et al., 2015 [37] Lamy et al., 2003 [21] Roivainem et al., 2013 [20] Neshige et al., 2015 [38] Labovitz et al., 2001 [26] Alberti et al., 2008 [58] Beghi et al., 2011 [25] De Herdt et al., 2011 [10] Procaccianti et al., 2012 [59] Goswami et al., 2012 [60] Denier et al., 2010 [6] Leung et al., 2017 [23]
first 48 h [20,21]. Several risk factors have been found, but differ according to the series (Table 1). However, the ones that appear consistently across the board include the presence of hemorrhage and cortical involvement, and stroke severity [as defined by either imaging data or initial National Institutes of Health Stroke Scale (NIHSS) scores]. In cases of endovascular therapy, hemorrhagic transformation has recently appeared to be a risk factor for seizures, but there was no information on the timing of presentation [22]. In our experience, ‘watershed’ topography is a strong and independent determinant of stroke-related early-onset seizures [6]. In one recent study, a cardioembolic origin of stroke and multifocal infarcts were also apparently major risk factors [23,24].
Anxiolytic, tobacco use
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Please cite this article in press as: Quirins M, et al. Epilepsy after stroke: Problems and a practical approach for clinicians. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.02.088
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3.4.
Outcomes
3.4.1. Is early post-stroke seizure a risk factor for vascular epilepsy? No data have consistently demonstrated that early poststroke seizures are a risk factor for later vascular epilepsy. For example, the study of Serafini et al. [37] in 2015 found an association between early seizures and vascular epilepsy in cases of hemorrhagic stroke. However, such a result was not found in the study conducted by Neshige et al. [38], which focused on hemorrhagic strokes. As for ischemic strokes, a relationship between early and late seizures has not been systematically found in any meaningful way. Fig. 2 – Intracranial vascular imaging of a patient with cerebral vasoconstriction syndrome and limb-shaking in the right leg shows a tight stenosis in the left middle cerebral artery (white arrow).
siology is a transient hemodynamic ischemia observed in cases of tight stenosis of the internal carotid artery or, less frequently, the intracranial vessels (Fig. 2). Midbrain strokes, whether ischemic or hemorrhagic, can provoke abnormal movements that generally, but not exclusively, mimic Parkinson’s syndrome [30–32].
3.3.3.
Electroencephalography
Standard 20-min EEG recordings of the acute phase of stroke usually show non-specific abnormalities, such as slow waves and periodic lateralized epileptiform discharges (PLEDs), but otherwise rarely contribute to a positive diagnosis of epileptic seizures [33]. Also, the optimal duration of EEG tracings for diagnosing early post-stroke seizures is still not well defined [33–35]. One study found paroxysmal epileptic figures on 17% of EEGs, whereas epileptic discharges (epileptic activity with consistent spatial and temporal organization) were recorded in only 2% of cases. None of the patients experienced any clinical seizures during hospitalization [34]. In our own patient database, 4 h of EEG recordings performed in 61 aphasic patients within 72 h of cerebral infarction yielded EEGs showing electrical epileptic seizures in 5% of cases. Clinical seizures were observed in the same number of patients, but not in those with epileptic seizures recorded by EEG (unpublished data). A recent study using video–EEG recordings showed that one-third of patients with early post-stroke seizures had no obvious clinical manifestations [36]. This questions the relevance of asymptomatic electrical seizures, although the first challenge to face in this issue is to identify the amplitude that defines the lack of clinical manifestation. Indeed, in the absence of a specifically oriented neurological examination based on the location of the discharge, it is probably preferable to speak of subclinical epileptic seizures rather than asymptomatic seizures. One example might be the symptomatology of an epileptic seizure limited to Broca’s area, which is clinically relevant only if the patient is able to speak. As present, further studies are needed to determine whether the presence of electrical epileptic discharges has any longterm effects.
3.4.2.
Impact of early post-stroke seizures on stroke outcomes
Here again the results of studies are contradictory, although most of the available data suggest a negative impact (Table 2). A meta-analysis published in 2016 revealed that early postischemic stroke seizures are associated with increased mortality [relative risk (RR): 2.45, 95% confidence interval (CI): 1.72–3.51] and morbidity, as defined by a Rankin Scale score between 3 and 5 (RR: 1.56, 95% CI: 1.29–1.88) [39].
4. Late-onset post-stroke (unprovoked) seizures Late-onset unprovoked seizures in the context of stroke now define vascular epilepsy, according to the new ILAE classification [40]. Thus, it is no longer necessary to wait for seizure relapse before starting antiepileptic drug treatment. In the elderly, the diagnosis of epilepsy is often difficult, particularly in patients who live alone, or have cognitive and/ or psychiatric comorbidities. In such a population, seizures may often be expressed through cognitive and confusional states, thereby further increasing diagnostic difficulties [2].
Table 2 – Summary of main study results: Is there a link between epilepsy after stroke and outcome? Studies Vespa et al., 2003 [61] Burneo et al., 2010 [62]
Mohamed et al., 2015 [63] Bryndziar et al., 2015 [64] Arboix et al., 2003 [65] Labovitz et al., 2001 [26] Huang et al., 2014 [13]
Serafini et al., 2015 [37] De Herdt et al., 2011 [10]
Main results Worsened deficit Increased edema Increased mortality Prolonged stay in hospital More severe disability at discharge Increased mortality No significant difference in disability Increased mortality More severe disability Increased in-hospital mortality No significant difference in mortality Increased mortality More frequent hospitalizations in intensive care units More frequent pneumopathy No significant difference in mortality No significant difference in mortality No significant difference in functional outcomes
Please cite this article in press as: Quirins M, et al. Epilepsy after stroke: Problems and a practical approach for clinicians. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.02.088
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The incidence of late-onset post-stroke seizures has been estimated at 8.2% for all types of strokes [41], while the rate at 5 years has been 9.5% for ischemic strokes, representing 10 to 30 times the risk found in the general population [9]. In hemorrhagic strokes, the rate is similar but slightly higher at an estimated 11.8% [19]. The risk factors identified for late epilepsy are similar to those for early seizures, and include age, hemorrhagic subtype, size and severity of stroke, and cortical involvement [1,41–43]. It should be noted, however, that intravenous thrombolysis is not associated with any increased risk of seizures [44]. Several recent studies have demonstrated an increased risk of stroke in adults with newly diagnosed epilepsy, especially in patients aged < 60 years. This suggests the possibility of occult cerebrovascular disease as a possible etiology of epilepsy associated with an increased risk of stroke [45,46]. In some cases, a common pathophysiological mechanism between stroke and epilepsy has also been suggested, although further studies are necessary before any conclusions can be drawn.
5.
Treatment issues
5.1.
Introducing drugs
Stroke patients are often elderly and have comorbidities, thereby requiring individual evaluation of the benefit–risk balance. This should always consider hepatic and renal function, drug interactions especially with anticoagulants and salicylates and, finally, the high susceptibility of this population to treatment side-effects. An important principle of antiepileptic treatment in the elderly is to ‘start low, go slow’ [2]. In animal models, a neuroprotective effect of antiepileptic dugs has been found, although such results have yet to be systematically replicated and demonstrated in human studies [47]. On the other hand, deleterious effects on neurological recovery have been repeatedly suggested with phenytoin, phenobarbital and benzodiazepines [48]. In cases of stroke associated with atheroma, it is necessary to be aware of antiepileptic drug-induced dyslipidemia (as seen with carbamazepine, phenytoin and valproate) [49]; in contrast, vascular epilepsy is usually easy to treat with monotherapy, as 80% of patients are seizure-free after 1 year [8].
5.2.
Indications
European recommendations were updated in February 2017 and, although the level of proof is low, these guidelines clarify treatment indications for ischemic stroke, hemorrhagic stroke and subarachnoid hemorrhage [9]. Prophylactic antiepileptic drugs are still not recommended regardless of type of stroke (ischemic, hemorrhagic, and even cerebral venous thrombosis) [9,50,51]. After the first early post-stroke seizure, the risk of recurrence is estimated to be 10–20%, and it is not recommended to start antiepileptic drug therapy except in cases of cerebral venous thrombosis [9,52]. However, with intracranial hemorrhage, Haapaniemi et al. [19] in 2014 developed the ‘CAVE’ scoring system to predict risk of seizure recurrence; scores range from 0 to 4, with one point given for each of the following:
5
cortical damage; age > 65 years; volume of hematoma > 10 mL; and early seizures. With a score of 0, the risk of unprovoked seizures is estimated to be 0.6%, and increases progressively up to 46.2% for a score of 4. Wider use of this scoring system might help to refine the indications for antiepileptic treatment following the first early seizure according to stroke subtype. While there are no European Stroke Organisation (ESO) recommendations for after a second early seizure, most teams tend to start antiepileptic drug treatment at that time. When starting treatment after an early post-stroke seizure, it is now recommended to stop medication once the acute stage is over or at the first post-stroke, 3-month visit because, as previously described, early seizures do not appear to be predictive of later vascular epilepsy [9]. However, the situation is somewhat different with lateonset seizures. In these cases, the risk of recurrence is estimated to be 70%, and antiepileptic treatment is now recommended after the first unprovoked seizure [9].
5.3.
Practical management
Antiepileptic treatment for stroke patients has never been specifically defined. In fact, any associated triggering factors for seizures need to be considered and treated that imply to correct metabolic disturbances, prevent withdrawal syndrome, avoid epileptogenic drug and get rid of any infectious diseases. However, there are no placebo-controlled randomized trials looking at better choices of antiepileptic drugs for patients with vascular epilepsy. Nevertheless, some evidence is available: given the numerous comparative studies conducted with phenytoin, the good clinical practice guidelines of the French Neurovascular Society (SFNV) recommend using only drugs with demonstrable efficacy in focal epilepsies, such as carbamazepine, oxcarbazepine, lamotrigine and levetiracetam. For the elderly, it is recommended to preferentially use lamotrigine and perhaps gabapentin [48]. Recent data have also favored lacosamide and zonisamide for elderly patients, although vascular epilepsy was not specifically studied [53,54]. One study carried out in Taiwan of patients with vascular epilepsy showed fewer emergency visits for those treated with valproic acid, carbamazepine or any of the new antiepileptic drugs compared with those treated with phenytoin [55] which, like carbamazepine and oxcarbazepine, is an enzyme inducer that can interact with other drugs. Phenytoin and valproate might also have negative cognitive effects. Moreover, phenytoin has demonstrated deleterious effects on neurological recovery in patients with subarachnoid and intracerebral hemorrhages [47,56]. A 2017 meta-analysis by Wang et al. [8] compared six studies of antiepileptic drug management in patients with stroke-associated epilepsy. Five antiepileptic drugs were involved, but it should be mentioned that the lamotrigine dosages were relatively low and that the extended-release form of carbamazepine was not used. The review showed:
similar efficacy with levetiracetam compared with carbamazepine for unprovoked seizures, and a better safety profile with lamotrigine compared with carbamazepine for both early- and late-onset seizures;
Please cite this article in press as: Quirins M, et al. Epilepsy after stroke: Problems and a practical approach for clinicians. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.02.088
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apparently similar efficacy with both levetiracetam and gabapentin, although there was no direct comparison; that phenobarbital caused prolongation of the QT interval compared with levetiracetam. A Chinese study in 2015 showed fewer early seizures in the acute phase of ischemic strokes with the use of statins [odds ratio (OR): 0.36, 95% CI: 0.20–0.62) [57]. Although the data were insufficient to establish patient management recommendations, they did provide further support of the benefits of statins in cases of cerebral ischemia, particularly when associated with atheroma.
6.
Conclusion
Seizures are commonly seen after strokes, but their treatment in this setting remains challenging. However, numerous studies are available and have allowed the development of recent guidelines for the management of post-stroke seizures and epilepsy. Nevertheless, some questions still remain, given the absence of randomized controlled trials with sufficient power from which to draw any conclusions. Clearly, further studies are still needed.
Disclosure of interest The authors declare that they have no competing interest.
references
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Please cite this article in press as: Quirins M, et al. Epilepsy after stroke: Problems and a practical approach for clinicians. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.02.088
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[29] Tomari S, Tanaka T, Ihara M, Matsuki T, Fukuma K, Matsubara S, et al. Risk factors for post-stroke seizure recurrence after the first episode. Seizure 2017;52:22–6. [30] Robles LA. Pure Hemiparkinsonism Secondary to Contralateral Lacunar Stroke in the Substantia Nigra. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc 2016;25(2):e20–1. [31] Martins WA, Marrone LCP, Fussiger H, Vedana VM, Cristovam R do A, Taietti MZ, et al. Holmes’ tremor as a delayed complication of thalamic stroke. J Clin Neurosci Off J Neurosurg Soc Australas 2016;26:158–9. [32] Bejr-Kasem Marco H, Lorenzo-Bosquet C, Alvarez-Sabin J, Hernandez-Vara J. Parkinsonism related to Percheron artery infarct. J Neurol Sci 2017;373:21–2. [33] Giroud M, Gras P, Fayolle H, Andre´ N, Soichot P, Dumas R. Early seizures after acute stroke: a study of 1640 cases. Epilepsia 1994;35(5):959–64. [34] Carrera E, Michel P, Despland P-A, Maeder-Ingvar M, Ruffieux C, Debatisse D, et al. Continuous assessment of electrical epileptic activity in acute stroke. Neurology 2006;67(1):99–104. [35] Van Putten MJAM, Tavy DLJ. Continuous quantitative EEG monitoring in hemispheric stroke patients using the brain symmetry index. Stroke 2004;35(11):2489–92. [36] Bentes C, Martins H, Peralta AR, Casimiro C, Morgado C, Franco AC, et al. Post-stroke seizures are clinically underestimated. J Neurol 2017;264(9):1978–85. [37] Serafini A, Gigli GL, Gregoraci G, Janes F, Cancelli I, Novello S, et al. Are early seizures predictive of epilepsy after a stroke? Results of a population-based study. Neuroepidemiology 2015;45(1):50–8. [38] Neshige S, Kuriyama M, Yoshimoto T, Takeshima S, Himeno T, Takamatsu K, et al. Seizures after intracerebral hemorrhage; risk factor, recurrence, efficacy of antiepileptic drug. J Neurol Sci 2015;359(1–2):318–22. [39] Xu T, Ou S, Liu X, Yu X, Yuan J, Huang H, et al. Association between seizures after ischemic stroke and stroke outcome: a systematic review and meta-analysis. Medicine (Baltimore) 2016;95(27):e4117. [40] Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55(4):475–82. [41] Jungehulsing GJ, Heuschmann PU, Holtkamp M, Schwab S, Kolominsky-Rabas PL. Incidence and predictors of poststroke epilepsy. Acta Neurol Scand 2013;127(6):427–30. [42] Bladin CF, Alexandrov AV, Bellavance A, Bornstein N, Chambers B, Cote´ R, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol 2000;57(11):1617–22. [43] Slapø GD, Lossius MI, Gjerstad L. Poststroke epilepsy: occurrence, predictors and treatment. Expert Rev Neurother 2006;6(12):1801–9. [44] Keller L, Hobohm C, Zeynalova S, Classen J, Baum P. Does treatment with t-PA increase the risk of developing epilepsy after stroke? J Neurol 2015;262(10):2364–72. [45] Wannamaker BB, Wilson DA, Malek AM, Selassie AW. Stroke after adult-onset epilepsy: a population-based retrospective cohort study. Epilepsy Behav EB 2015;43:93–9. [46] Chang C-S, Liao C-H, Lin C-C, Lane H-Y, Sung F-C, Kao C-H. Patients with epilepsy are at an increased risk of subsequent stroke: a population-based cohort study. Seizure 2014;23(5):377–81. [47] Goldstein LB. Common drugs may influence motor recovery after stroke. The Sygen in acute stroke study investigators. Neurology 1995;45(5):865–71. [48] Ryvlin P, Montavont A, Nighoghossian N. Optimizing therapy of seizures in stroke patients. Neurology 2006;67(12 Suppl 4):S3–9.
[49] Vyas MV, Davidson BA, Escalaya L, Costella J, Saposnik G, Burneo JG. Antiepileptic drug use for treatment of epilepsy and dyslipidemia: Systematic review. Epilepsy Res 2015;113:44–67. [50] Powers WJ, Derdeyn CP, Biller J, Coffey CS, Hoh BL, Jauch EC, et al. 2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: a Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015;46(10):3020–35. [51] Sykes L, Wood E, Kwan J. Antiepileptic drugs for the primary and secondary prevention of seizures after stroke. Cochrane Database Syst Rev 2014;(1):CD005398. [52] Ferro JM, Bousser M-G, Canha˜o P, Coutinho JM, Crassard I, Dentali F, et al. European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis – endorsed by the European Academy of Neurology. Eur J Neurol 2017;24(10):1203–13. [53] Rainesalo S, Ma¨kinen J, Raitanen J, Peltola J. Clinical management of elderly patients with epilepsy; the use of lacosamide in a single center setting. Epilepsy Behav EB 2017;75:86–9. [54] Sarkis RA, Nicolas J, Lee JW. Tolerability of lacosamide or zonisamide in elderly patients with seizures. Seizure 2017;49:1–4. [55] Huang YH, Chi NF, Kuan YC, Chan L, Hu CJ, Chiou HY, et al. Efficacy of phenytoin, valproic acid, carbamazepine and new antiepileptic drugs on control of late-onset post-stroke epilepsy in Taiwan. Eur J Neurol 2015;22(11):1459–68. [56] Naidech AM, Kreiter KT, Janjua N, Ostapkovich N, Parra A, Commichau C, et al. Phenytoin exposure is associated with functional and cognitive disability after subarachnoid hemorrhage. Stroke 2005;36(3):583–7. [57] Guo J, Guo J, Li J, Zhou M, Qin F, Zhang S, et al. Statin treatment reduces the risk of poststroke seizures. Neurology 2015;85(8):701–7. [58] 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):715–20. [59] 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. [60] Goswami RP, Karmakar PS, Ghosh A. Early seizures in firstever acute stroke patients in India: incidence, predictive factors and impact on early outcome. Eur J Neurol 2012;19(10):1361–6. [61] Vespa PM, O’Phelan K, Shah M, Mirabelli J, Starkman S, Kidwell C, et al. Acute seizures after intracerebral hemorrhage: a factor in progressive midline shift and outcome. Neurology 2003;60(9):1441–6. [62] Burneo JG, Fang J, Saposnik G. Investigators of the Registry of the Canadian Stroke Network. Impact of seizures on morbidity and mortality after stroke: a Canadian multicentre cohort study. Eur J Neurol 2010;17(1):52–8. [63] Mohamed C, Kissani N. Early seizures in acute stroke. Pan Afr Med J 2015;20:136. [64] Bryndziar T, Sedova P, Kramer NM, Mandrekar J, Mikulik R, Brown RD, et al. Seizures Following Ischemic Stroke: Frequency of Occurrence and Impact on Outcome in a Long-Term Population-Based Study. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc 2016;25(1):150–6. [65] Arboix A, Comes E, Garcı´a-Eroles L, Massons JB, Oliveres M, Balcells M. Prognostic value of very early seizures for inhospital mortality in atherothrombotic infarction. Eur Neurol 2003;50(2):78–84.
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General review
Epilepsy after stroke: Definitions, problems and a practical approach for clinicians M. Quirins *, C. Dussaule, C. Denier, P. Masnou Service de neurologie adulte, CHU Biceˆtre, 78, avenue du Ge´ne´ral Leclerc, 94270 Le Kremlin Biceˆtre, France
info article
abstract
Article history:
Stroke, whether ischemic or hemorrhagic, is the main etiology of epilepsy in the elderly.
Received 23 January 2018
However, incidences and outcomes differ according to stroke subtype and delay of onset
Accepted 28 February 2018
following the stroke. While the medical literature is extensive, it is not always consistent,
Available online xxx
and many questions still remain regarding risk factors and management of vascular epilepsy. Thus, the present report here is an overview of the clinical aspects of vascular
Keywords:
epilepsy using a practical approach that integrates data from meta-analyses and the more
Stroke
recently published expert recommendations. # 2018 Elsevier Masson SAS. All rights reserved.
Seizure Early onset Late-onset seizure Vascular epilepsy
1.
Introduction
Stroke is the most common etiology for seizures and epilepsy in the elderly, representing nearly half of all symptomatic epilepsies in patients aged > 60 years [1–3]. Post-stroke seizures can manifest either soon after the onset of stroke or be delayed, and few definitions are necessary. First, ‘seizures at onset’ arise at the same time as stroke; ‘early seizures’ appear within 7 days according to a recent definition, but as they correspond to acute symptomatic seizures [4], there is no need to even mention epilepsy; and finally, ‘late-onset seizures’ or ‘unprovoked seizures’ manifest after 7 days. According to the latest revised classification of the International League Against Epilepsy (ILAE), a lateonset seizure in the context of stroke defines vascular epilepsy, making it no longer necessary to wait for a second seizure [5].
Distinguishing between these different types of seizures is not only a semantic problem, but also one based on different pathophysiological mechanisms. Early post-stroke seizures are associated with biochemical changes: cytotoxic neurotransmitters are released and induce neuronal hyperexcitability in the area of the penumbra by increasing extracellular glutamate, and intracellular sodium and calcium. In contrast, late-onset seizures have a pathophysiological mechanism similar to that of post-traumatic seizures, involving gliosis and hemosiderin deposits [1,6]. Considerable data are available on post-stroke seizures, but the results are somewhat variable, thereby requiring several caveats for interpretations and comparisons [7]: first, the definition of early seizures is variable: while usually between 7 and 14 days, it can nonetheless range from 2 days to 1 month [8]; second, early and late post-stroke seizures are not always distinguishable by stroke subtype (cerebral infarction, sub-
* Corresponding author. E-mail address: [email protected] (M. Quirins). https://doi.org/10.1016/j.neurol.2018.02.088 0035-3787/# 2018 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Quirins M, et al. Epilepsy after stroke: Problems and a practical approach for clinicians. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.02.088
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arachnoid or intracranial hemorrhage, cerebral venous thrombosis); and finally, from an electrophysiological point of view, until recently, it was almost never stated whether seizures had been defined clinically, electrically or by both. Furthermore, as there are no randomized controlled trials with sufficient power, any evidence to support recommendations is limited [9]. Thus, the present report is an overview of the clinical aspects of vascular epilepsy using a practical approach that integrates data from meta-analyses and more recently published recommendations (Fig. 1).
2.
Seizures at stroke onset
Seizures manifest at onset in 4.3–6.2% of ischemic strokes, and in 10.7–15.6% of hemorrhagic strokes [10–12]. The main risk factor for these seizures is hemorrhagic stroke, although female gender, younger age and less-severe motor deficit have also proved to be significant risk factors [13]. One study of prehospital diagnostic accuracy in stroke found that, in 76 cases of epileptic seizures, six strokes associated with seizure at onset went undiagnosed while, on the other hand, stroke was erroneously mentioned in 14 patients [14]. It is important to bear in mind the possibility of seizures at stroke onset so as
not to prematurely preclude eligible patients from receiving intravenous thrombolysis or mechanical thrombectomy. Previously, contraindications for tissue plasminogen activator (tPA) included epileptic seizures to avoid carrying out the procedure in cases of postictal deficit mimicking stroke. However, since then, magnetic resonance imaging (MRI) and perfusion sequences have been developed that allow more precise diagnoses to be made. It has also been shown that, in cases of seizures not associated with ischemia, tPA is a safe procedure [15,16]. Thus, to date, recommendations from various learned societies have been revised, and now specify that if the residual deficit can be attributed to ischemia and not only postictal deficit, then seizures are no longer a contraindication for intravenous thrombolysis [17,18].
3.
Early post-stroke seizures
3.1.
Epidemiology
The incidence of early post-stroke seizures is highly variable depending on differences in methodology, as discussed previously. Rates are, on average, between 2% and 4% of ischemic strokes [8], and between 10% to 16% of intracranial hemorrhages [17–19]. Around half of cases manifest within the
Fig. 1 – A practical summary of seizures after stroke. US: unprovoked seizure; LTG: lamotrigine; GBP: gabapentin; LEV: levetiracetam; LCS: lacosamide; ZNS: zonisamide; CBZ: carbamazepine; OCZ: oxcarbazepine. Please cite this article in press as: Quirins M, et al. Epilepsy after stroke: Problems and a practical approach for clinicians. Revue neurologique (2018), https://doi.org/10.1016/j.neurol.2018.02.088
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Other factors
Alcoholism Watershed infarcts Cardioembolism, multiple territory infarcts
No # No # # # # # Yes # # #
Hyperglycemia Hyponatremia
Yes # Yes # # # # # No # # # # No No Yes No No No Onset only No No No #
Young age Size/severity
# Yes Yes Yes No Yes No Onset only Yes Yes No #
I: ischemic stroke; H: intracerebral hemorrhage; SAH: subarachnoid hemorrhage; US: unprovoked seizure; #: not studied or not applicable. Intracerebral or hemorrhagic transformation of ischemic stroke.
Differential diagnoses
These include, in the first place, stroke recurrence, thereby requiring regular (control) brain imaging in case of emergencies. In the context of recent stroke, blood sugar disorders (hypo- or hyperglycemia) can induce changes on both neurological examination and seizures. In particular, metabolic disorders are purveyors of arousal fluctuations. It is also well known that toxic and metabolic encephalopathies can induce asterixis (distal negative myoclonus), which should not be confused with epileptic clonic seizures. In such cases, EEG recordings are essential for making the diagnosis and avoiding the unnecessary addition of an antiepileptic drug that can worsen encephalopathy. Two other less-well-known conditions responsible for differential diagnoses, but yet still not abnormal epileptic movements, are limb-shaking and midbrain strokes or acute insults of the subthalamic nuclei. Limb-shaking is clinically manifested by limb tremor mimicking myoclonia, but manifesting exclusively on standing (orthostatism). The pathophy-
a
3.3.2.
US only Yes # Yes Yes Yes Yes Yes Yes Yes Yes #
Clinical presentation
The clinical diagnosis of early seizures is sometimes easy, especially in cases of clonic manifestations on the side of hemiplegia. However, this situation is unusual, and the symptomatology is more often non-specific, with fluctuating arousal or transient worsening on neurological examination [2]. Thus, in these cases, diagnosis can be difficult and, in our experience, standard 20-min electroencephalography (EEG) is rarely contributory.
Cortical involvement
3.3.1.
Hemorrhagea
Diagnosis
Table 1 – Risk factors for acute symptomatic seizures: summary of some study results.
3.3.
Yes # Yes # No Yes Yes # Yes Yes # Yes
Early post-stroke seizures are mostly focal and with or without consciousness impairment [4,6]. Status epilepticus is uncommon, manifesting in only 0.14–1.1% of strokes, but may be the initial presentation in 0.12% of cases, representing 5–27% of this type of seizures [25–27]. On the other hand, 22% of new-onset status epilepticus cases are related to stroke. However, the influence of status epilepticus on the prognosis remains controversial: one study showed a twofold greater risk of mortality at 6 months [28], whereas another showed no increase in mortality [27]. It is also unclear whether early poststroke status epilepticus is a risk factor for late-onset seizures [27,29].
I, H, SAH I I H I, H, SAH I, H I, H H I, H I, H I I
Type of seizures
Stroke subtype
3.2.
Serafini et al., 2015 [37] Lamy et al., 2003 [21] Roivainem et al., 2013 [20] Neshige et al., 2015 [38] Labovitz et al., 2001 [26] Alberti et al., 2008 [58] Beghi et al., 2011 [25] De Herdt et al., 2011 [10] Procaccianti et al., 2012 [59] Goswami et al., 2012 [60] Denier et al., 2010 [6] Leung et al., 2017 [23]
first 48 h [20,21]. Several risk factors have been found, but differ according to the series (Table 1). However, the ones that appear consistently across the board include the presence of hemorrhage and cortical involvement, and stroke severity [as defined by either imaging data or initial National Institutes of Health Stroke Scale (NIHSS) scores]. In cases of endovascular therapy, hemorrhagic transformation has recently appeared to be a risk factor for seizures, but there was no information on the timing of presentation [22]. In our experience, ‘watershed’ topography is a strong and independent determinant of stroke-related early-onset seizures [6]. In one recent study, a cardioembolic origin of stroke and multifocal infarcts were also apparently major risk factors [23,24].
Anxiolytic, tobacco use
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3.4.
Outcomes
3.4.1. Is early post-stroke seizure a risk factor for vascular epilepsy? No data have consistently demonstrated that early poststroke seizures are a risk factor for later vascular epilepsy. For example, the study of Serafini et al. [37] in 2015 found an association between early seizures and vascular epilepsy in cases of hemorrhagic stroke. However, such a result was not found in the study conducted by Neshige et al. [38], which focused on hemorrhagic strokes. As for ischemic strokes, a relationship between early and late seizures has not been systematically found in any meaningful way. Fig. 2 – Intracranial vascular imaging of a patient with cerebral vasoconstriction syndrome and limb-shaking in the right leg shows a tight stenosis in the left middle cerebral artery (white arrow).
siology is a transient hemodynamic ischemia observed in cases of tight stenosis of the internal carotid artery or, less frequently, the intracranial vessels (Fig. 2). Midbrain strokes, whether ischemic or hemorrhagic, can provoke abnormal movements that generally, but not exclusively, mimic Parkinson’s syndrome [30–32].
3.3.3.
Electroencephalography
Standard 20-min EEG recordings of the acute phase of stroke usually show non-specific abnormalities, such as slow waves and periodic lateralized epileptiform discharges (PLEDs), but otherwise rarely contribute to a positive diagnosis of epileptic seizures [33]. Also, the optimal duration of EEG tracings for diagnosing early post-stroke seizures is still not well defined [33–35]. One study found paroxysmal epileptic figures on 17% of EEGs, whereas epileptic discharges (epileptic activity with consistent spatial and temporal organization) were recorded in only 2% of cases. None of the patients experienced any clinical seizures during hospitalization [34]. In our own patient database, 4 h of EEG recordings performed in 61 aphasic patients within 72 h of cerebral infarction yielded EEGs showing electrical epileptic seizures in 5% of cases. Clinical seizures were observed in the same number of patients, but not in those with epileptic seizures recorded by EEG (unpublished data). A recent study using video–EEG recordings showed that one-third of patients with early post-stroke seizures had no obvious clinical manifestations [36]. This questions the relevance of asymptomatic electrical seizures, although the first challenge to face in this issue is to identify the amplitude that defines the lack of clinical manifestation. Indeed, in the absence of a specifically oriented neurological examination based on the location of the discharge, it is probably preferable to speak of subclinical epileptic seizures rather than asymptomatic seizures. One example might be the symptomatology of an epileptic seizure limited to Broca’s area, which is clinically relevant only if the patient is able to speak. As present, further studies are needed to determine whether the presence of electrical epileptic discharges has any longterm effects.
3.4.2.
Impact of early post-stroke seizures on stroke outcomes
Here again the results of studies are contradictory, although most of the available data suggest a negative impact (Table 2). A meta-analysis published in 2016 revealed that early postischemic stroke seizures are associated with increased mortality [relative risk (RR): 2.45, 95% confidence interval (CI): 1.72–3.51] and morbidity, as defined by a Rankin Scale score between 3 and 5 (RR: 1.56, 95% CI: 1.29–1.88) [39].
4. Late-onset post-stroke (unprovoked) seizures Late-onset unprovoked seizures in the context of stroke now define vascular epilepsy, according to the new ILAE classification [40]. Thus, it is no longer necessary to wait for seizure relapse before starting antiepileptic drug treatment. In the elderly, the diagnosis of epilepsy is often difficult, particularly in patients who live alone, or have cognitive and/ or psychiatric comorbidities. In such a population, seizures may often be expressed through cognitive and confusional states, thereby further increasing diagnostic difficulties [2].
Table 2 – Summary of main study results: Is there a link between epilepsy after stroke and outcome? Studies Vespa et al., 2003 [61] Burneo et al., 2010 [62]
Mohamed et al., 2015 [63] Bryndziar et al., 2015 [64] Arboix et al., 2003 [65] Labovitz et al., 2001 [26] Huang et al., 2014 [13]
Serafini et al., 2015 [37] De Herdt et al., 2011 [10]
Main results Worsened deficit Increased edema Increased mortality Prolonged stay in hospital More severe disability at discharge Increased mortality No significant difference in disability Increased mortality More severe disability Increased in-hospital mortality No significant difference in mortality Increased mortality More frequent hospitalizations in intensive care units More frequent pneumopathy No significant difference in mortality No significant difference in mortality No significant difference in functional outcomes
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The incidence of late-onset post-stroke seizures has been estimated at 8.2% for all types of strokes [41], while the rate at 5 years has been 9.5% for ischemic strokes, representing 10 to 30 times the risk found in the general population [9]. In hemorrhagic strokes, the rate is similar but slightly higher at an estimated 11.8% [19]. The risk factors identified for late epilepsy are similar to those for early seizures, and include age, hemorrhagic subtype, size and severity of stroke, and cortical involvement [1,41–43]. It should be noted, however, that intravenous thrombolysis is not associated with any increased risk of seizures [44]. Several recent studies have demonstrated an increased risk of stroke in adults with newly diagnosed epilepsy, especially in patients aged < 60 years. This suggests the possibility of occult cerebrovascular disease as a possible etiology of epilepsy associated with an increased risk of stroke [45,46]. In some cases, a common pathophysiological mechanism between stroke and epilepsy has also been suggested, although further studies are necessary before any conclusions can be drawn.
5.
Treatment issues
5.1.
Introducing drugs
Stroke patients are often elderly and have comorbidities, thereby requiring individual evaluation of the benefit–risk balance. This should always consider hepatic and renal function, drug interactions especially with anticoagulants and salicylates and, finally, the high susceptibility of this population to treatment side-effects. An important principle of antiepileptic treatment in the elderly is to ‘start low, go slow’ [2]. In animal models, a neuroprotective effect of antiepileptic dugs has been found, although such results have yet to be systematically replicated and demonstrated in human studies [47]. On the other hand, deleterious effects on neurological recovery have been repeatedly suggested with phenytoin, phenobarbital and benzodiazepines [48]. In cases of stroke associated with atheroma, it is necessary to be aware of antiepileptic drug-induced dyslipidemia (as seen with carbamazepine, phenytoin and valproate) [49]; in contrast, vascular epilepsy is usually easy to treat with monotherapy, as 80% of patients are seizure-free after 1 year [8].
5.2.
Indications
European recommendations were updated in February 2017 and, although the level of proof is low, these guidelines clarify treatment indications for ischemic stroke, hemorrhagic stroke and subarachnoid hemorrhage [9]. Prophylactic antiepileptic drugs are still not recommended regardless of type of stroke (ischemic, hemorrhagic, and even cerebral venous thrombosis) [9,50,51]. After the first early post-stroke seizure, the risk of recurrence is estimated to be 10–20%, and it is not recommended to start antiepileptic drug therapy except in cases of cerebral venous thrombosis [9,52]. However, with intracranial hemorrhage, Haapaniemi et al. [19] in 2014 developed the ‘CAVE’ scoring system to predict risk of seizure recurrence; scores range from 0 to 4, with one point given for each of the following:
5
cortical damage; age > 65 years; volume of hematoma > 10 mL; and early seizures. With a score of 0, the risk of unprovoked seizures is estimated to be 0.6%, and increases progressively up to 46.2% for a score of 4. Wider use of this scoring system might help to refine the indications for antiepileptic treatment following the first early seizure according to stroke subtype. While there are no European Stroke Organisation (ESO) recommendations for after a second early seizure, most teams tend to start antiepileptic drug treatment at that time. When starting treatment after an early post-stroke seizure, it is now recommended to stop medication once the acute stage is over or at the first post-stroke, 3-month visit because, as previously described, early seizures do not appear to be predictive of later vascular epilepsy [9]. However, the situation is somewhat different with lateonset seizures. In these cases, the risk of recurrence is estimated to be 70%, and antiepileptic treatment is now recommended after the first unprovoked seizure [9].
5.3.
Practical management
Antiepileptic treatment for stroke patients has never been specifically defined. In fact, any associated triggering factors for seizures need to be considered and treated that imply to correct metabolic disturbances, prevent withdrawal syndrome, avoid epileptogenic drug and get rid of any infectious diseases. However, there are no placebo-controlled randomized trials looking at better choices of antiepileptic drugs for patients with vascular epilepsy. Nevertheless, some evidence is available: given the numerous comparative studies conducted with phenytoin, the good clinical practice guidelines of the French Neurovascular Society (SFNV) recommend using only drugs with demonstrable efficacy in focal epilepsies, such as carbamazepine, oxcarbazepine, lamotrigine and levetiracetam. For the elderly, it is recommended to preferentially use lamotrigine and perhaps gabapentin [48]. Recent data have also favored lacosamide and zonisamide for elderly patients, although vascular epilepsy was not specifically studied [53,54]. One study carried out in Taiwan of patients with vascular epilepsy showed fewer emergency visits for those treated with valproic acid, carbamazepine or any of the new antiepileptic drugs compared with those treated with phenytoin [55] which, like carbamazepine and oxcarbazepine, is an enzyme inducer that can interact with other drugs. Phenytoin and valproate might also have negative cognitive effects. Moreover, phenytoin has demonstrated deleterious effects on neurological recovery in patients with subarachnoid and intracerebral hemorrhages [47,56]. A 2017 meta-analysis by Wang et al. [8] compared six studies of antiepileptic drug management in patients with stroke-associated epilepsy. Five antiepileptic drugs were involved, but it should be mentioned that the lamotrigine dosages were relatively low and that the extended-release form of carbamazepine was not used. The review showed:
similar efficacy with levetiracetam compared with carbamazepine for unprovoked seizures, and a better safety profile with lamotrigine compared with carbamazepine for both early- and late-onset seizures;
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apparently similar efficacy with both levetiracetam and gabapentin, although there was no direct comparison; that phenobarbital caused prolongation of the QT interval compared with levetiracetam. A Chinese study in 2015 showed fewer early seizures in the acute phase of ischemic strokes with the use of statins [odds ratio (OR): 0.36, 95% CI: 0.20–0.62) [57]. Although the data were insufficient to establish patient management recommendations, they did provide further support of the benefits of statins in cases of cerebral ischemia, particularly when associated with atheroma.
6.
Conclusion
Seizures are commonly seen after strokes, but their treatment in this setting remains challenging. However, numerous studies are available and have allowed the development of recent guidelines for the management of post-stroke seizures and epilepsy. Nevertheless, some questions still remain, given the absence of randomized controlled trials with sufficient power from which to draw any conclusions. Clearly, further studies are still needed.
Disclosure of interest The authors declare that they have no competing interest.
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