Cerebrovascular Disease; A Leading Cause of Epilepsy

*Kaoru Obata, Kazuaki Sato, Hiroya Ohara and Masako Kinoshita*

#### **Abstract**

Various types of cerebrovascular diseases can result in epilepsy in any age, especially in the elderly. Besides well-known cause of epilepsy as large cerebral infarction involving cerebral cortex and intracerebral hemorrhage, there are growing evidences of roles of subcortical infarction, chronic subdural hematoma, and superficial siderosis of the central nervous system in the pathogenesis of epilepsy. We review here the epidemiology and possible predictors of epilepsy in each type of cerebrovascular lesions and summarize the characteristics of semiology and electroencephalography findings in order to take early treatment strategy. Additionally, relevance of acute-symptomatic seizures and status epilepticus to epilepsy is discussed.

**Keywords:** epilepsy, cerebrovascular diseases, cerebral infarction, intracranial hemorrhage, stroke, provoked seizures, acute symptomatic seizures, early seizures, late seizures

#### **1. Introduction**

Various kinds of brain insults are associated with an increased risk for development of seizures and epilepsy. In adults, a probable etiology of approximately 50% of new-onset seizures can be determined. Cerebrovascular diseases are the most common risk factors of epilepsy (21%), followed by tumors (11%) and traumatic brain injury (7%) [1]. In children and adolescents of 0–19 years of age, the leading epilepsy etiologies are static encephalopathies (38.2%), stroke (12.1%), traumatic brain injury (11.4%), and infection (8.6%) [2].

The traditional definition of stroke is based on clinical characteristics of the sudden onset of loss of focal neurological dysfunction due to infarction or hemorrhage in the relevant part of the brain, retina, or spinal cord, lasting longer than 24 hours [3]. Stroke is classified into cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage (SAH).

Post-stroke seizures have been classified as either early seizures or late seizures, depending on the interval from stroke onset to seizure onset. In the field of stroke, the latent period of two weeks has been most commonly used to distinguish between early seizures and late seizures [4]. Approximately 5–10% of patients with stroke present early seizures within the first two weeks and about half of them occur during the first day after the stroke [5, 6]. In the field of epilepsy, the International League Against Epilepsy (ILAE) proposes a recommendation to define acute symptomatic seizures as seizures occurring within one week subsequent to acute damage to the brain, caused by such as stroke, traumatic brain injury, anoxic encephalopathy, and intracranial surgery [7]. Seizures occurring at least two weeks after stroke are called late or remote symptomatic seizures [4, 8]. Epilepsy is a brain disorder with an enduring preposition to generate epileptic seizures, usually applicable to patients having two or more unprovoked seizures occurring at least 24 hours apart. In addition, ILAE updated the practical definition of epilepsy in 2014 to apply also to a condition of one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years [9]. Therefore, occurrence of an unprovoked late seizure is necessary and sufficient for the diagnosis of post-stroke epilepsy (PSE) because of a high risk of recurrence; such patients are recommended to be treated with antiepileptic medication under the diagnosis of epilepsy [9].

Depending on the type of underlying cerebrovascular disease, 3–30% of patients who experience stroke may develop PSE [10]. The risk to develop epilepsy after stroke is the highest during the first two years, but still elevated even 10 years after stroke [11].

Status epilepticus is a medical emergency that has high mortality rate (approximately 20%) [12]. Classically status epilepticus was defined as a condition characterized by an epileptic seizure sufficiently prolonged or repeated at sufficiently brief intervals so as to produce an unvarying and enduring epileptic condition. In 2015, ILAE proposed the new definition of status epilepticus as follows. Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. Because of incomplete evidence, each time point should be considered as the best estimates currently available. In the case of convulsive status epilepticus, t1 at 5 minute and t2 at 30 minutes are suggested based on animal experiments and clinical research [13]. Patients with status epilepticus rarely recover spontaneously; therefore they should be treated with antiepileptic drugs as soon as possible.

Status epilepticus occurs in 1.5–2.8% of stroke patients [14, 15]. In the older adults (≧65 years of age), 52.3% of status epilepticus are caused by stroke [16]. In the older adults (≧60 years of age), semiology of status epilepticus is less frequently generalized tonic–clonic seizures compared to younger adults (33% vs. 63%, p = 0.001); on the other side, non-convulsive status epilepticus with coma are exclusively seen in older patients (10.3% vs. 0%, p = 0.02) [17]. In this chapter, we reviewed the epidemiology and possible predictors of epilepsy in each type of cerebrovascular diseases. The characteristics of semiology and electroencephalography (EEG) findings which enable us to take early treatment strategy are summarized. Relevance of acute-symptomatic seizures and status epilepticus to epilepsy is also discussed.

#### **2. What kinds of vascular lesions can cause epilepsy?**

#### **2.1 General risk factors of poststroke seizures and epilepsy**

Cerebrovascular disease is the most common etiology of acute symptomatic seizures and secondary epilepsy in adults, accounting for approximately 11% of epilepsy diagnosis [18].

*Cerebrovascular Disease; A Leading Cause of Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.95119*

All types of cerebrovascular diseases can cause early or late seizures. Among them, the common causes of epilepsy are cerebral infarction, intracerebral hemorrhage, and SAH (**Table 1**). As a genetic risk factor of PSE, the relationship between PSE and the ALDH2 (aldehyde dehydrogenase 2) rs671 polymorphism is known [48].

The risk factors for early seizures after stroke include intracerebral hemorrhage, cerebral infarction with hemorrhagic transformation, stroke severity, and alcoholism [49].

The risk factors for PSE include cortical involvement (visual neglect, dysphagia, field defect, and so on), stroke severity indies at presentation, including low Glasgow Coma Scale, incontinence, or poor Barthel Index, hemorrhagic lesions, young age (< 65 years), and stroke subtype, particularly total anterior circulation infarcts [11]. Abraira et al. pointed that NIHSS score more than 4 at the stroke presentation and post-stroke status epilepticus duration more than 16 hours might predict of PSE in patients with early-onset post-stroke status epilepticus [50].

#### **2.2 Cerebral infarction**

Cerebral infarction can occur at any age, with the greatest risk being during the first week after birth. In adults, about 70–85% of cerebrovascular diseases are ischemic. Etiological subtypes of cerebral infarction are classified according to the TOAST classification (**Table 2**) [51], the ASCOD phenotyping system [52], and the Causative Classification System [53]. Most cases of PSE are due to arterial ischemic stroke [54], accounting for up to 9% of incident cases of epilepsy [55].

In ASCOD, every patient should be graded using 5 categories: A (atherosclerosis); S (small-vessel disease); C (cardiac pathology); O (other cause), and D (dissection) [52]. With the Causative Classification System classification of ischemic stroke etiology, ischemic stroke is classified as the following; large artery atherosclerosis, cardio-aortic embolism, small artery occlusion, other causes, and undetermined causes [53].


*a Post-traumatic seizure/epilepsy.*

*b Seizures with hemorrhage at presentation.*

*c Ratio of convulsion.*

*d Ratio of seizures.*

#### **Table 1.**

*Prevalence of early seizure, late seizure, and epilepsy in each cerebrovascular disease.*


#### **Table 2.**

*The TOAST classification of subtypes of acute ischemic stroke [51].*

Early seizure occurrence is associated with hemorrhagic transformation and stroke severity. Late seizure is associated with cortical involvement and stroke severity [56]. The SeLECT score is proposed to predict the risk of late seizures after ischemic stroke, using only five well-defined parameters (Severity of stroke, Largeartery atherosclerotic etiology, Early seizures, Cortical involvement, and Territory of middle cerebral artery involvement) [57]. The overall risk of late seizures was 4% at 1 year and 8% at 5 years after stroke. Based on the estimation, patients with the SeLECT value of 7 points or more have more than 60% risk of seizures within 5 years after stroke, which is higher than the practical definition of epilepsy by ILAE (at least 60% over the next 10 years) [9], even though the patients have no unprovoked seizures. The risk factors for epilepsy after ischemic stroke include early seizures, stroke severity, stroke subtype, stroke location (anterior circulation infarct and cortical involvement), stroke recurrence, artery dissection and established coronary disease [56, 58]. Patients receiving thrombolytic or intra-arterial reperfusion therapies for acute ischemic stroke are at higher risk of epilepsy [59]. Post-stroke seizures can be sometimes associated with small vessel disease. The risk of developing seizures is more strongly related to the localization of lacunar infarctions in the hemispheric white matter (leukoaraiosis) than in the basal ganglia or in the brain stem [60]. Branch atheromatous disease could also have an association with late seizures [61].

#### **2.3 Intracerebral hemorrhage**

Early seizures were seen in 31% of patients with spontaneous intracerebral hemorrhage who were evaluated with continuous electroencephalographic monitoring and over half had purely electrographic seizures only [22]. The incidence of PSE after intracerebral hemorrhage is between 8.1 and 13.5% [4, 25]. Seizures secondary to intracerebral hemorrhage are relatively common like this and likely underdiagnosed event that may have little impact on in-hospital mortality and morbidity [62]. Nonconvulsive electrographic seizures may be associated with hematoma expansion [22].

The risk factors for seizures following intracerebral hemorrhage are associated with hemorrhage volume, hemorrhage location within the cerebrum, cortical involvement and the severity of neurological deficits [10]. Surgery for an intracerebral hemorrhage is an additional risk for the development of late seizures [63].

For patients with spontaneous intracerebral hemorrhage, clinical early seizures should be treated with antiepileptic drugs [64]. When the patients have a change in mental status, the evaluation with EEG is recommended. If the patients have electrographic seizures on EEG, they should be treated with antiepileptic drugs [64].

#### *Cerebrovascular Disease; A Leading Cause of Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.95119*

Current clinical guidelines do not recommend the routine use of prophylactic antiepileptic drugs for spontaneous intracerebral hemorrhage [64] because there is no evidence to improve neurological function [65].

Periodic discharges on EEG could be associated with cortical intracerebral hemorrhage and poor outcome [22].

## **2.4 Subarachnoid hemorrhage**

Early seizures may be seen in up to 20% of patients after aneurysmal SAH, and more commonly in association with intracerebral hemorrhage, hypertension, and middle cerebral and anterior communicating artery aneurysms [26]. Early seizures after SAH occur most commonly in the first 24 hours [26]. The actuarial risk of epilepsy after SAH was 18% by the first year, 23% by the second year, and 25% by the fifth year in the survivors of SAH [28]. Aneurysm location most associated with the development of SAH-related epilepsy is middle cerebral artery at the M1 branch and artery bifurcation [66]. The risk factors for epilepsy after aneurysmal SAH include the rupture of aneurysms in the anterior circulation, a young age, intracerebral hemorrhage, a poor neurological outcome, and hemosiderosis [29, 66]. Severe Hunt and Hess score as well as intraventricular hemorrhage elevate the risk of having a seizure after SAH [67]. The degree of neurological impairment and presence of an early seizure soon after the time of SAH have been identified as a risk factor for post-SAH epilepsy [68].

Nonconvulsive seizures following SAH cause transient brain hypoxia, increased intracranial pressure, and increased blood pressure [69]. Although evidence is not sufficient yet, guidelines recommend to consider the prophylactic use of antiepileptic medication except phenytoin (PHT) in the immediate post-hemorrhagic period and to consider the routine use of antiepileptic medication for patients with known risk factors for late seizures such as prior seizure, intracerebral hematoma, intractable hypertension, infarction, or aneurysm at the middle cerebral artery, though longterm use is not recommended [26]. Importantly, PHT should be avoided for the prophylaxis of early seizure following aneurysmal SAH because of known association with vasospasm, worsening of cognitive outcomes, and infarctions [70]. Recently, levetiracetam (LEV) is increasingly used for the prophylaxis of early seizures [26, 70].
