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Current Treatment Options in Cardiovascular Medicine DOI 10.1007/s11936-013-0236-7 Cerebrovascular Disease and Stroke (C Helgason and M Alberts, Section Editors) Migraine, Stroke and Epilepsy: Underlying and Interrelated Causes, Diagnosis and Treatment Aida Rodriguez-Sainz, MD Ana Pinedo-Brochado, MD Jose L. Sa´nchez-Menoyo, MD Javier Ruiz-Ojeda, MD Ines Escalza-Cortina, MD Juan Carlos Garcia-Monco, MD * Address *Department of Neurology, Hospital de Galdakao-Usansolo, 48960 Vizcaya, Spain Email: [email protected] * Springer Science+Business Media New York 2013 Keywords Stroke I Migraine I Epilepsy I Seizures I Vascular epilepsy Opinion statement Migraine, epilepsy and stroke are highly prevalent neurological disorders, often comorbid. They share diverse pathophysiological mechanisms that explain the use of similar drugs on certain occasions (i.e., the use of antiepileptic drugs in migraine prevention). Migraine with aura represents a risk for ischemic stroke, and avoiding contraceptives, tobacco use, and ergot alkaloids should be advised in those patients. Epilepsy bears a bidirectional relationship with headache. Only three entities are considered as seizure-related headaches: migraine-triggered sei- zure (migralepsy), hemicrania epileptica, and post-ictal headache. Topiramate (100200 mg daily) and valproic acid (5001,000 mg daily) are first-line drugs in migraine prevention, while older antiepileptics have no use in this setting. Stroke is the most common cause of symptomatic epilepsy in the adult. Therapy with lamotrigine, gabapentine, and levetiracetam is advised in late-onset (2 weeks after stroke) stroke-seizures, while early-onset seizures usually do not require therapy. Introduction Migraine, stroke and epilepsy represent, together with dementia, the most common neurological disorders. They are characterized by paroxysmal episodes, either transient (migraine attacks, seizures and transient is-

Migraine, Stroke and Epilepsy: Underlying and Interrelated Causes, Diagnosis and Treatment

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Page 1: Migraine, Stroke and Epilepsy: Underlying and Interrelated Causes, Diagnosis and Treatment

Current Treatment Options in Cardiovascular MedicineDOI 10.1007/s11936-013-0236-7

Cerebrovascular Disease and Stroke (C Helgason and M Alberts, Section Editors)

Migraine, Stroke and Epilepsy:Underlying and Interrelated Causes,Diagnosis and TreatmentAida Rodriguez-Sainz, MDAna Pinedo-Brochado, MDJose L. Sanchez-Menoyo, MDJavier Ruiz-Ojeda, MDInes Escalza-Cortina, MDJuan Carlos Garcia-Monco, MD*

Address*Department of Neurology, Hospital de Galdakao-Usansolo, 48960 Vizcaya, SpainEmail: [email protected]

* Springer Science+Business Media New York 2013

Keywords Stroke I Migraine I Epilepsy I Seizures I Vascular epilepsy

Opinion statement

Migraine, epilepsy and stroke are highly prevalent neurological disorders, oftencomorbid. They share diverse pathophysiological mechanisms that explain theuse of similar drugs on certain occasions (i.e., the use of antiepileptic drugs inmigraine prevention). Migraine with aura represents a risk for ischemic stroke,and avoiding contraceptives, tobacco use, and ergot alkaloids should be advisedin those patients. Epilepsy bears a bidirectional relationship with headache. Onlythree entities are considered as seizure-related headaches: migraine-triggered sei-zure (migralepsy), hemicrania epileptica, and post-ictal headache. Topiramate(100–200 mg daily) and valproic acid (500–1,000 mg daily) are first-line drugsin migraine prevention, while older antiepileptics have no use in this setting.Stroke is the most common cause of symptomatic epilepsy in the adult. Therapywith lamotrigine, gabapentine, and levetiracetam is advised in late-onset (2 weeksafter stroke) stroke-seizures, while early-onset seizures usually do not requiretherapy.

IntroductionMigraine, stroke and epilepsy represent, together withdementia, the most common neurological disorders.

They are characterized by paroxysmal episodes, eithertransient (migraine attacks, seizures and transient is-

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chemic attacks [TIAs]) or permanent (stroke) braindysfunction sharing some pathophysiological mecha-nisms [1, 2].

Their high prevalence favors their coexistence, andin fact several studies have shown a higher comorbid-ity than expected by chance [3•, 4•, 5]. Furthermore,migraine has been proposed as a risk factor for stroke,

as a trigger of seizures, and seizures secondary tostroke are commonplace.

Our objective was to carry out an updated review ofthe relationship between these three entities, focusingon their shared pathophysiological mechanisms, rep-resenting potential therapeutic targets with the conse-quent management advice.

Migraine and strokeEpidemiology

The prevalence of migraine in the general population is 12–17 % in womenand around 6 % in men [6, 7], and stroke occurs in 2–5 % of the generalpopulation. The incidence of stroke in migraine patients, however, is higherthan expected, which has led to the proposal that migraine represents anindependent risk factor for stroke.

Migraine as a vascular risk factorSeveral studies and meta-analysis describe migraine as a vascular riskfactor, not only for stroke, but also for myocardial infarction and peripheralartery disease [5].

The absolute risk of stroke in migraineurs is 3.8 cases per 100,000people and year, which doubles the risk of nonmigraineurs. The risk isassociated to migraine with aura (MA) (OR: 2.51), while migrainewithout aura does not represent a significantly increased risk [8].

Regarding ischemic stroke, women with MA have a higher risk than men(OR: 2.89), particularly young women (G45 years).

Smoking and oral contraceptives increase the risk of stroke (OR: 9.03 and7.02, respectively) [8]. MA also seems to increase the risk of hemorrhagicstrokes (OR: 2,25), particularly in older women [4•].

Migraine seems particularly associated to ischemic strokes in the posteriorcirculation in young women, and to a lesser degree, to lacunar strokes.Overall, prognosis is favorable. In contrast, brain hemorrhages convey asomber prognosis.

PathophysiologyThere are several hypotheses about the mechanisms involved in the associa-tion of migraine and stroke [8, 9••].

The cortical spreading depression (CSD) theory proposes that migraineaura is the consequence of a synchronous neuronal depolarization withonset in the occipital cortex and slowly propagating forward (Fig. 1).

CSD causes changes in cerebral perfusion in three phases. An initial hy-peremia lasting a few minutes is followed by a longer oligemia of 1–2 hours duration, and a final brief hyperemia (Fig. 2).

During oligemia, the cerebral blood flow is reduced, but does not reachthe ischemic threshold. However, a sustained and severe CSD in suscepti-ble individuals might result in brain ischemia (Fig. 3).

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Figure 1. DCP, depolarization wave (2–6 mm/min).

Figure 2. An initial hyperemia lasting a few minutes fol-lowed by a longer oligemia of 1–2 hours duration, and afinal brief hyperemia.

Figure 3. A sustained and severe cortical spreading depression(CSD) in susceptible individuals might result in brain ischemia.

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Patients suffering from familial hemiplegicmigraine harbor geneticmutations(CACNA1A, SCN1A, ATP1A2) that affect the potassium and glutamate homeo-stasis, increasing neuronal excitability and decreasing the CSD threshold [9••].

Another hypothesis points to a dysfunction of vascular endothelium. InMA,there is a decrease in the number, migration, and aging of endothelial precursorcells responsible for endothelial repair and prevention of plaque formation thatresults in a pro-thrombotic and pro-inflammatory state leading to vasculardisease [8]. This hypothesis is applicable to CADASIL, a brain small-vessel dis-order characterized by MA, ischemic strokes, and vascular dementia [9••].

Increased platelet activation and aggregation is another plausible theory. Sev-eral studies have found increased serum platelet-activating factor (PAF) levelsduringMOattacks [10], and interictal levels of a thromboxane A2metabolite andcirculating platelet-leukocyte aggregates [11, 12]. Furthermore, high on-aspirinplatelet reactivity, or aspirin resistance, has been reported in migraine [13].

The presence of patent foramen ovale in MA, allowing for the passage ofparadoxical embolisms, as well as of substances such as serotonin, has beenproposed to be responsible for stroke in these patients, and would explaintheir high prevalence of patent foramen ovale (PFO) (54 %) [8]. Retro-spective studies have evaluated the effect of PFO closure on migraine, sug-gesting a significant benefit [14–17], particularly among patients withmigraine with aura. A reduction between 54 and 71 % in the frequency ofmigraine attacks of patients with migraine with aura and of 50–62 % inmigraine without aura was observed after PFO closure [14, 17] However,contrary to these findings are the results of the first prospective study of PFOclosure for migraine, the MIST trial, which did not find an improvement inmigraine after foramen ovale closure [18].

Migraine as an etiology of strokeWomen with frequent migraines usually harbor silent ischemic brain lesions,as shown by MRI studies. They mainly involve the occipital lobes, the cere-bellum, and the deep white matter [19]. Yet, the presence of these ischemiclesions has not been demonstrated to confer a higher stroke risk [4•].

The International Headache Society (IHS) defines migraine infarction asoccurring during a migraine attack with similar symptoms to the patient’saura, but lasting at least 60 minutes and with evidence of an ischemic lesionconsistent with the clinical features. They are usually located in the posteriorcirculation, but sometimes lacunar or retinal strokes appear [20].

Cervical artery dissection may also result in stroke, and is associated witha two-fold increased risk of cervical artery dissection among migraineurs. Arecent study shows that migraine without aura is more common amongpatients with cervical artery dissection and stroke as compared to strokepatients without dissection [21]. On the other hand, cervical artery dissectioncommonly presents with headache, sometimes resembling migraine.

Treatment adviceThere is not a special approach to the treatment or prevention of stroke inmigraine patients. Control of concurrent cardiovascular risk factors, such asarterial hypertension, dyslipidemia or diabetes, is highly recommended.Smoking cessation and avoiding hormonal contraceptives should be rec-

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ommended in women under the age of 45 with migraine with aura. [22].Primary prevention with aspirin is not indicated in migraine patients. It

should be borne in mind that some of the drugs employed in stroke pre-vention (i.e., dipyridamole) may in turn cause headache.

Regarding the management of migraine attacks, it should be consideredthat ergot alkaloids are associated with a higher risk of ischemic brainlesions, conveying a higher mortality. This is not the case with triptans, al-though their use is not recommended in patients who have had a stroke, dueto their potential vasoconstrictor effect [8].

At present, there is not enough evidence to recommend PFO closure of inmigraine patients [18, 23], even though there is literature suggesting that atleast some patients, particularly those with migraine with aura, may benefitfrom this procedure.

Migraine and epilepsy

Migraine and epilepsy are key members of a large family of episodic disordersthat also include periodic paralyses, cardiac arrhythmias and episodic move-ment disorders. In these episodic disorders, patients are affected with symptomssporadically. Their hallmark is their paroxysmal nature, and between attacks,affected individuals are symptom-free. They are often due to defects in iontransport proteins [24].

Migraine and seizure attacks may evolve in four comparable stages withprodromal symptoms, aura, ictal episode (seizure or headache), and a pos-tictal phase. Occasionally, the attacks fail to stop, resulting in status epilep-ticus or migrainosus. There are a large number of similar triggers for bothdiseases such as stress, sleep-related factors, photic stimulation, hormonalchanges and alcohol or dietary factors [25].

Comorbidity of epilepsy and migraineMigraine and epilepsy are both common neurological disorders, the firstbeing more prevalent [26], and their comorbidity is well known. A recentstudy has shown that 56 (3 %) of 1,795 children with headache also hadepilepsy [27]. Overall, the prevalence of epilepsy in individuals with mi-graine has been reported to be higher than the population prevalence of 0.5–1 %. However, a recent Italian multicenter study with 1,167 subjects found aprevalence similar to that of the general population [7].

Partial and cryptogenic epilepsies are associatedwithhigher rates ofmigrainethan idiopatic epilepsy. The strong association between posttraumatic epilepsyand migraine is believed to occur because head injury is a risk for both condi-tions [25, 28].

Clinical aspects and terminologyOnly three specific entities of seizures-related headaches (SRH) are consid-ered in the International Classification for Headache Disorders (ICHD-II) ofthe International Headache Society [29]: migraine-triggered seizure (migra-lepsy), hemicrania epileptica, and post-ictal headache .

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The term migralepsy describes a condition in which seizures occur duringclassical migraine aura (migraine-triggered seizure). There have been reportsof only about 60 cases of possible migralepsy described in children andadults [30, 31]. By reviewing those cases, rigorously ictal electroencepha-lography (EEG) data were normal in 4 % and not recorded in 68 %, and byapplying the ICHD-II criteria strictly, these authors reduced them to only onemigralepsy case [31]. Indeed, most of the previous reports of “migralepsy”corresponded to occipital seizures that mimic migraine with aura [32]. As aconsequence, the term ‘migralepsy’ has recently been criticized by manyauthors [3•, 33].

Recently, the term “ictal epileptic headache” (IEH) has been proposed [34].IEH is a rarely described phenomenon consisting of migraine/headache asthe sole manifestation of a seizure. It has been observed in a small number ofpatients with focal seizures (predominantly from the occipital lobes), or withnonconvulsive status epilepticus [35]. This specific type of SRH is so rare thatwas not included in the classification of the International League AgainstEpilepsy (ILAE) nor in the ICHD-II [35, 36]. In those cases, the EEG re-cording varied considerably, with no specific findings [37]. From a syn-dromic point of view, most patients had a symptomatic posterior focalepilepsy [35]. Recently, Fanella et al. described one of the few EEG-docu-mented ictal epileptic headaches in generalized idiopathic epilepsy [38].

Hemicrania epileptica is recognized as an ipsilateral headache, with migrain-ous features occurring as an ictal manifestation of the seizure discharge. Di-agnosis requires the simultaneous onset of headache with EEG demonstrateddischarge [37].

SRH can be divided, according to their temporal relationship to the epi-leptic attack, in peri-ictal and interictal headaches. Peri-ictal can be also di-vided into pre-ictal, ictal and postictal headache. When headache occursimmediately after a seizure, it is called postictal headache (post-IH) [39], andis the most frequent headache type associated with seizures. Preictal head-aches occur in 5–15 %, ictal in 3–5 %, postictal in 10–50 % and interictal in25–60 % of cases [40].

Regarding the quality of SRH, an important correlation between mi-graine-type headaches both in post-IH and peri-ictal headaches was foundin pediatric studies [41]. In adults, the migrainous features were common inpost-IH in patients with or without a history of interictal migraine [7].

Migraine-like post-IH occurs not only following occipital seizures, but al-so following generalized tonic-clonic seizures and temporal lobe seizures[42].

Although amigraine-type headache is a common post-ictal phenomenon, itis often neglected because of the dramatic manifestation of the seizure [3•].

Evidence suggests that comorbid migraine is associated with a worseprognosis of epilepsy, and it was found that epilepsy-migraine patientshad a longer duration of the disease and a lower response to antiepileptictreatment than patients with epilepsy without migraine [43].

PathophysiologyMigraine and epilepsy are episodic disorders that share many clinical featuresand pathophysiological mechanisms. Many studies support the hypothesis of

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excessive neocortical cellular excitability as the main pathological mecha-nism underlying the onset of both diseases. The attacks begin with hyper-synchronous neuronal firing. In epilepsy, the hypersynchronous activitycontinues, whereas in migraine with aura there is cortical spreading depres-sion (CSD). CSD seems to be the connecting point between migraine andepilepsy [44–46]. A paroxysmal change in cortical neuronal activity mayoccur during a migraine attack or epileptic seizure; hyperexcitation occurs inepilepsy, whereas in migraine, hypoexcitation and hyperexcitation occur se-quentially as rebound phenomena (spreading depression). In both CSD andin epileptic focus, the onset and propagation are triggered when some neu-rophysiological events reach a certain threshold, which is lower for CSD thanfor seizures. Recurrent seizures might also predispose patients to CSD,thereby increasing the occurrence of of peri-ictal and post-ictal migraine-typeheadache [3•, 45]. Therefore, it has been proposed that seizures can in someinstances trigger trigeminovascular pain mechanisms as occurs in migraine[25].

Glutamate is a critical mediator of the hyperexcitability in both focal seiz-ures and migraine. In focal epilepsy, seizure generation and spreading ismediated by synaptically released glutamate acting on AMPA receptors,whereas triggering of CSD depends on NMDA receptors, and spreading doesnot require synaptic transmission [25].

A further similarity between migraine and epilepsy is that some antiepi-leptic drugs (AEDs) are useful in both conditions. AEDs reduce neuronalhyperexcitability by various mechanisms. There is extensive evidence thatdivalproex sodium (valproate) and topiramate are effective in preventingmigraine attacks. Gabapentin and pregabalin may also be effective in mi-graine therapy. Other AEDs that have been reported to be useful in migraineprophylaxis are levetiracetam and zonisamide. By contrast, others AEDs, in-cluding phenytoin, oxcarbazepine, vigabatrin and clonazepam, are not ef-fective in migraine prophylaxis. Thus, AEDs that act primarily via use-dependent block of voltage-gated sodium channels or that act via GABAergicmechanisms appear to influence hyperexcitability mechanisms that are notrelevant to migraine. In any case, it is noteworthy that both in epilepsy andmigraine, a proportion of patients are pharmacoresistant (around 30 % inboth conditions) [25, 47–50]. On the other hand, the vagus nerve stimula-tion (VNS) is useful in both conditions. Several small clinical series and caserepots reveled that VNS can reduce migraine attacks in patients who had VNSdevice implantation for epilepsy [51, 52].

GeneticsMigraine has long been known to have a strong inherited component, butuntil recently no accepted linkage genetic marker variants have been estab-lished for the common forms; a similar lack of information applies to thecommon forms of epilepsy. Recently, genome-wide association studies havebegun to identify genetic variants that confer increased risk for migraine [53].

The identification of genes responsible for both conditions is perhaps thestrongest evidence for shared underlying mechanisms [25]. Recently, twochromosomal loci (14q12-q23 and 12q24.2-q24.3) have been discovered tobe associated with migraine and epilepsy in a Finnish family whose members

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had epilepsy, migraine or both [54].Strong support for a shared genetic basis comes from familial hemiplegic

migraine (FHM). Three different genes cosegregate with FHM. Epilepsy hasbeen reported in all three FHM types. The first to be described was CAC-NA1A. CACNA1A mutations account for about half of all cases of FHM. Thesecond FHM gene to be described was ATP1A2. Among the forms of FHM,this type has the most frequent association with epilepsy (approximately20 % of families). The third FHM gene is SCN1A, which encodes the pore-forming α1-subunit of neuronal type I voltage-gated sodium channelNav1.1. [25, 55].

Treatment adviceSeveral antiepileptic drugs (topiramate and valproic acid) are successfully usedin migraine prevention. They decrease neuronal hyperexcitability through di-verse mechanisms that would explain their shared effectiveness in both condi-tions. Topiramate is most often used at a daily dose of 100–200 mg, while thedaily dose of valproic acid ranges between 500 and 1000 mg. Phenytoin,oxcarbazepine, vigabatrin, lamotrigine, clonazepam and gabapentin have notbeen clearly useful in migraine prevention [56], and should not be used in thissetting. There is an urgent need for more studies in migraine prevention, sincethe current therapeutic armamentarium is quite restricted.

The use of VNS may be a novel approach in therapy of intractable mi-graine, but further randomized trials are necessary to evaluate this treat-ment option [51, 52].

The treatment of migraine in FHM and non-familiar HM is similar to oth-er common varieties of migraine. Although controversial for its vasocon-strictor effect, triptans can be prescribed when headaches are not relievedwith common analgesics, and ergot alkaloids are best avoided. There is noeffective treatment for the severe and often prolonged aura symptoms[57].

Stroke and epilepsyEpidemiology

Vascular epilepsy is the most frequent cause of symptomatic epilepsy in theadult. It justifies 11 % of the adult-onset epilepsy, reaching 33 % in the el-derly [58]. A population-based study in Rochester, Minnesota, found that31.7 % of symptomatic seizures occurred in patients aged 65 or older [59].

Stroke as a risk factor for seizuresStroke increases the risk of seizures 23–25 times [60]. Early stroke-relatedseizures (occurring within the first 2 weeks after stroke) are due to a bio-chemical dysfunction, while late seizures are secondary to structural glioticchanges in the brain and represent the true vascular epilepsy [61]. Moststudies show that brain hemorrhages, subarachnoid bleeding, and intracra-nial venous thrombosis convey a higher risk factor than ischemic stroke [62].Whether this is true for late vascular epilepsy is unclear.

Regarding location, cortical involvement has been found to be themost con-sistent predictor for early seizures. However, seizures are present in 2.6–3.5% oflacunar infarctions. [62]. The presence of cortical tissue islets within the area of

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ischemic infarction represents another risk factor for stroke-related seizures [63].Stroke severity is directly associated with the risk of vascular epilepsy [64]. Earlyseizures occurring during the first week after stroke are associated to an increasedrisk of late vascular seizures and epilepsy, perhaps because they tend to appear inthe more severe strokes. About 54–66 % of patients with late seizures willeventually develop epilepsy [65]. However, a retrospective study has suggestedthat early-onset seizures do not require chronic therapy [66].

Although still a matter of debate, some studies link early stroke-relatedseizure to an increased mortality and dependence [67, 68]. Late-onset seiz-ures are associated to a poorer stroke prognosis, and vascular epilepsy hasbeen suggested as a risk factor for cognitive decline [69]. Furthermore, cog-nitive decline and neurological worsening may occur after prophylacticphenytoin therapy in patients with subarachnoid hemorrhage [70].

Elderly-onset seizures in subjects without prior seizures, also known asheraldic seizures, may be the initial manifestation of a silent cerebrovascu-lar disorder [71].

Status epilepticus develops in 9–19 % of patients who have suffered aprior stroke and 61 % of status developing in the elderly are due tostroke [72]. Status epilepticus confers a higher disability if present in thefirst 7 days after stroke, with a higher risk of recurrence and death thanlater-onset status (after 7 days post stroke).

Treatment adviceProphylactic antiepileptic therapy for brain hemorrhage, but not for ischemicstroke, has been proposed by some guidelines.

There is no consensus as to when to start antiepileptic therapy after afirst stroke-related seizure, or which drug to use. While some antiepilepticdrugs may have a neuroprotective effect in vitro, most of the first-gener-ation drugs may negatively influence stroke recovery and patients’ prog-nosis [73••]. This should be weighed against the consequences of asecond seizure. The decision should be individualized, taking into accountthe characteristics of the first episode and the patient’s preferences [74].

Early-onset, focal seizures may not require therapy unless they recur orevolve into status epilepticus. In contrast, late-onset seizures usually requiretherapy for 3–6 months, due to their likely recurrence [75].

Regarding the drug of choice, first-line drugs may interfere with secondarystroke prevention. Phenytoin, carbamazepine, phenobarbital, primidone areenzymatic inducers, while valproate and benzodiazepines show a high proteinbinding, thus interacting with warfarin and antiplatelet agents. Lamotrigine,gabapentine, and levetiracetam are preferred in vascular-related seizures, par-ticularly in the elderly, due to their lower potential for interactions (level ofevidence A) [76–78].

Conclusions

Stroke risk is increased in young women with migraine with aura, in whomsmoking and oral contraceptives should be avoided.

Migraine and epilepsy are comorbid, episodic disorders sharing patho-physiological mechanisms leading to neuronal hyperexcitability that

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explains the use of similar drugs in both disorders. Their overlap is supportedby genetic studies; FHM and other recent genetic findings confirm the linkbetween migraine and epilepsy. The suspicion of a migraine-triggered seizurerequires an electroencephalogram during that migraine attack to demonstratethe epileptic discharge in true cases of “ictal epileptic headache”.

Vascular epilepsy is the most frequent cause of symptomatic epilepsy inthe adult. Stroke increases significantly the risk of seizures, which can ap-pear early (less than 2 weeks) or late, and may somber stroke prognosis.Their management should be individualized. Cortical involvement has beenfound to be the most consistent predictor for early seizures. While early-onset, focal seizures may not require therapy, a 3–6 month therapy withnewer drugs (lamotrigine, gabapentine, and levetiracetam) is recommendedfor late-onset stroke-related seizures.

DisclosureDr. Aida Rodriguez-Sainz reported no conflicts of interest relevant to this article.

Dr. Ana Pinedo-Brochado reported no conflicts of interest relevant to this article.Dr. Jose L. Sánchez-Menoyo reported no conflicts of interest relevant to this article.Dr. Javier Ruiz-Ojeda reported no conflicts of interest relevant to this article.Dr. Ines Escalza-Cortina reported no conflicts of interest relevant to this article.Dr. Juan Carlos Garcia-Monco reported no conflicts of interest relevant to this article.

References and Recommended ReadingPapers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

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