• Ischemic etiologies
• Hemorrhagic etiologies
• Other etiologies
• Epidemiology of stroke
• Incidence and risk factors for seizures
• Types of seizures
• Assessment of seizures
• Differential diagnosis
• Treatment of seizures
• Phenytoin
• Phenobarbital
• Carbamazepine
• Valproate
• Other AEDs
• Special situations
• Prognosis
• References

Ischemic infarcts result in neuronal death from localized loss of blood flow. Cell death occurs when energy-dependent processes, such as maintaining ionic gradients across cellular and intracellular membranes, fail. Excitotoxicity mediated by glutamate receptors also contributes.12 In addition, as the damage heals, inflammatory processes are activated and can cause further neuronal damage.

A frequent cause of ischemic infarcts is progressive atherosclerosis leading to critical stenosis or occlusion of major arteries, such as the internal carotid, vertebral, or basilar arteries. An unclear percentage of such vascular lesions may actually produce infarcts by the phenomenon of artery-to-artery embolisms arising from unstable plaques or thromboses.7,13

Cardiogenic emboli most often arise from a friable clot occurring on a diseased valvular or myocardial surface. They frequently lodge in large arteries at branching points, such as the origin of the middle cerebral artery (MCA) and its major subdivisions or the basilar bifurcation at the origin of the posterior cerebral arteries (PCAs). Less common are clots that result from nonbacterial thrombotic endocarditis or septic emboli from infectious endocarditis.

Embolic strokes usually affect the cortex of gray-white junction, where blood flow is highest and end arteries predominate; cortical involvement would be more likely to precipitate seizures and epilepsy than subcortical lesions.

Arterial dissection, occurring because of trauma to the vessel (sometimes trivial or forgotten), connective tissue disorders, or both, can cause embolic or thrombotic stroke in the involved vascular territory.

A common cause of ischemic stroke is progressive stenosis of small vessels, classically from damage to the vascular media caused by chronic hypertension, a process termed lipohyalinosis (probably a form of atherosclerosis). This usually affects the penetrating arteries that branch off the MCA or basilar artery, causing “lacunar” infarcts of the basal ganglia, deep white matter, or brain stem. Damage to these areas is less likely to cause acute symptomatic seizures or epilepsy than are strokes that affect cortex directly.

Global cerebral hypoperfusion that occurs in the setting of stenotic vessels can result in focal infarcts, usually occurring at cortical and subcortical border zone or “watershed” areas between territories of the major blood vessels, especially the anterior cerebral artery and MCA, or the MCA and PCA. Severe hypoperfusion or cardiac arrest can also cause selective damage to these areas, particularly if large vessels are narrowed from atherosclerosis, but more commonly results in widespread damage, sometimes diffusely affecting the middle layers of cortex, termed laminar necrosis. Less complete insults may cause selective damage of the hippocampus and cerebellum. Acute symptomatic seizures or status epilepticus (SE), especially myoclonic status, is common after hypoxic-ischemic insults.14

Hypercoagulable states, such as may be associated with malignancy, collagen vascular diseases, or genetic abnormalities of the thrombolytic system, cause in situ thrombosis of small or large vessels, often multiple. They are also associated with cardiogenic emboli from nonbacterial thrombotic endocarditis.13 Certain types of coagulation defects may promote venous rather than arterial thrombosis, leading to venous infarcts or, among patients with cardiac septal defects, arterial emboli.

Vasospasm is thought to be the main mechanism by which migraine causes occasional stroke. Platelet aggregation may also be a triggering event. Migrainous infarction is a rare complication of a common condition and is more likely to occur in those with focal neurologic symptoms as a component of their usual migraine.15 Vasospasm can also occur as a complication of angiography. (Patients with migraine may have a higher risk.) Branches of the PCA are most often affected.

Systemic or cerebral vasculitis is another potential cause of vasospasm and is due to autoimmune disease or drug abuse, particularly of cocaine.15 Inflammation of the arterial walls can also cause hemorrhage, although this is more common with inflammation caused by infections.

Nearly any kind of ischemic process, if rapidly reversible, can result in temporary dysfunction without permanent damage, manifested as a transient ischemic attack (TIA). Magnetic resonance imaging (MRI) has demonstrated that permanent structural changes (i.e., infarcts) can occur with TIAs lasting well under 24 hours, however, even though the clinical deficits appear to resolve completely.7 Therefore, not just acute symptomatic seizures but also epilepsy can result from a clinical TIA.

Hemorrhagic conversion of ischemic infarcts occurs when the vessel wall itself is sufficiently damaged to disturb its integrity. Clinically, this is more likely to occur with embolic infarcts than with other types. Furthermore, because current means of treating or preventing ischemic infarcts interfere with clot formation or maintenance, these therapeutic measures also pose a risk of hemorrhage. This risk is low for antiplatelet agents and moderate for anticoagulants and thrombolytic agents.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

• An arterial leak results in a concussive insult to nearby neurons and axons, leading to neuronal dysfunction and, if sufficiently severe, neuronal death.
• If the leak is not quickly sealed, then intracranial pressure rises, ultimately to the level of arterial pressure, and cerebral perfusion is precluded until communication between the arterial and extra-arterial cerebral space is ended. This elimination of perfusion pressure can result in global, multifocal, or localized ischemia.
• Locally, a blood clot constitutes a mass lesion that exerts pressure on nearby neural and vascular structures and sometimes sufficiently interferes with arterial or venous blood flow to cause an infarct.
• After intracerebral hemorrhage, as with ischemic infarcts, the inflammatory system is activated to dispose of cellular and hematologic debris, and this can cause vasospasm.
• Blood products result in chronic exposure of neurons to iron-containing compounds, which may lead to peroxidation of lipid membranes and promote excitatory ionic currents.8

Within each category, cortical involvement increases the likelihood of seizures. Larger lesions and more severe deficits are associated with a higher risk of seizures and epilepsy in most, but not all, circumstances

Congenital vascular malformations

Congenital vascular malformations are a common cause of intracerebral hemorrhage, especially in younger people. These are usually divided into three types:

• Arteriovenous malformations (AVMs) have a direct arterial-to-venous connection without an intervening capillary bed. Most eventually become symptomatic, with the most common presentation being hemorrhage (40–50%) and the next most common being seizures (17–40%), especially in younger people and perhaps in those with larger malformations.4,16 AVMs may also produce progressive, and at times transient, ischemic deficits via a steal phenomenon from surrounding normal tissue.
• Cavernous angiomas consist of vascular channels lined by endothelium without intervening neural tissue. Seizures are the most common presentation, occurring in at least 40–70% of patients.16 A sizable proportion, however, are incidental findings on MRI and are estimated to occur in 0.5% of the general population.17 Diagnosis usually depends on a characteristic heterogeneous pattern with evidence of surrounding blood products, implying at least minor hemorrhage.
• Venous angiomas are aberrant venous channels that communicate with the normal venous system. Symptoms are uncommon, but of those venous angiomas that become symptomatic, most present with seizures, except those located in the cerebellum, which are the most likely ones to hemorrhage.

A fourth type of vascular malformation, capillary telangiectasias, consists of dilated capillary structures with intervening neural tissue. These are most often located in the pons and are rarely symptomatic.

Subarachnoid hemorrhage

Subarachnoid hemorrhage may result from AVMs or from coagulation or platelet defects, but the most common cause by far is rupture of a saccular aneurysm, thought to result from an area of congenital weakness in the arterial wall, usually located at branch points near the circle of Willis. The most common locations of these aneurysms are the junction of the posterior communicating artery and internal carotid artery and the anterior communicating artery. Next most common are the proximal middle cerebral artery and then the posterior circulation.7 Thought to be congenital, they are present in perhaps 5% of the population. The likelihood of rupture increases markedly with advancing age, as well as with hypertension and smoking.

Approximately one-third of ruptures are immediately fatal, another one-third result in significant disability, and another one-third of patients recover without major disability.

The major risks after the initial bleed are

• rebleeding (may be prevented by surgery to occlude the aneurysmal neck)
• vasospasm, causing focal or multifocal cerebral ischemia (This ischemia may in some cases be prevented by increasing perfusion pressure, but it is unsafe to do so unless the aneurysm has been secured.)
• hydrocephalus (early or late)

Acute symptomatic seizures may occur at the time of the initial bleed, when they may be confused with syncope resulting from transient cessation of cerebral perfusion, caused by the acute rise in intracranial pressure to equal the systemic pressure. Epilepsy and acute symptomatic seizures may be related to hemorrhages that occur parenchymally, as well as in the subarachnoid space. Intracerebral extension of the hemorrhage is often associated with rupture of aneurysms that involve the anterior communicating artery and damage the orbitofrontal cortex.

Subarachnoid and subdural bleeding can result from another type of anomaly, dural arteriovenous fistulas, which may be acquired as a result of trauma or other insult. These can also cause seizures and epilepsy, but the usual presentation is chronic headache.18

Intracerebral hemorrhage

Intracerebral hemorrhages are most commonly due to acute and chronic hypertension. In these patients, most of the hemorrhages are located in the basal ganglia, especially the putamen. Although lobar hemorrhages are more likely to produce seizures and epilepsy, some deep hemorrhages, especially those involving the caudate,19 may also lead to seizures.

A substantial proportion of lobar hemorrhages may in fact be due to a different source of vascular damage than that produced by hypertension. The terms cerebral amyloid angiopathy (CAA), cerebral congophilic angiopathy, and cerebrovascular amyloidosis refer to a clinicopathologic entity characterized by hyaline eosinophilic staining properties.20 CAA is implicated as the cause of primary nontraumatic intracerebral hemorrhage in as many as 10–15% of patients over the age of 60 years and in nearly 20% of patients over the age of 70 years.21 This pathology may also produce seizures in the absence of gross hemorrhage; petechial hemorrhage is suspected.22

Other causes of intracerebral hemorrhage include coagulopathies. These may be congenital, such as the hemophilias, or acquired, often as a result of treatment with anticoagulants or thrombolytic agents.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Cerebral venous occlusions may occur spontaneously in patients with a hypercoagulable state (including pregnancy or recent parturition) or in those with intracranial infections, especially in parameningeal locations, such as the mastoid. These occlusions diminish local blood flow and typically produce hemorrhagic infarctions that do not conform to the usual arterial territories. Cortical vein thrombosis commonly produces acute symptomatic seizures, but epilepsy is a much less common sequela.28–30

The term hypertensive encephalopathy refers to an acute cerebrovascular syndrome precipitated by sudden, severe hypertension.11 When systemic blood pressure is raised suddenly, there is a loss of cerebral autoregulation from forced dilatation of cerebral resistance vessels. Pathologically, these vessels show abnormal permeability to protein, and the surrounding brain shows swelling of astrocytes, primarily of cortical layers 2 and 3.10 This process results in localized cerebral edema, often affecting the parieto-occipital regions and causing focal deficits and often acute symptomatic seizures.23,24 Patients usually make a good recovery. Although petechial hemorrhage is common, epilepsy rarely follows these insults. It is important to realize that the degree of hypertension need not be extreme, as long as it is unusually high for a given patient.

A clinically and radiographically similar process occurs among patients on immunosuppressant therapy, even in those with only minor elevations of blood pressure. Apparently, the immunosuppressant itself can directly affect vessel wall permeability.

Eclampsia may result from a similar pathophysiologic process.25 Again, acute symptomatic seizures are common, but epilepsy is rare. Treatment with magnesium is recommended (see Special situations). Magnesium can block the NMDA subtype of excitatory glutamate receptors, but it is not clear that systemic administration has such an effect across the blood-brain barrier, so its use in this syndrome may succeed because of its effects on the underlying vascular pathophysiology.25,26

A special situation that is closely related to the processes previously discussed is that of postendarterectomy hyperperfusion syndrome. This occurs usually a day or two after successful carotid endarterectomy. It is characterized by acute headache, hemispheric edema ipsilateral to the surgery, and acute symptomatic seizures.27 Pathophysiology is thought to be rapid restoration of perfusion pressure in a distal circulation that has been accustomed to much lower perfusion, resulting in a loss of autoregulation and associated dysfunction. Lowering blood pressure is the mainstay of treatment. Therapy with antiepileptic drugs is also important, to prevent focal seizures and the further localized blood flow increases associated with them.

Within each stroke category, cortical involvement increases the likelihood of seizures. This is not surprising in view of the well-established conception of seizures as cortical events. In addition, larger lesions and more severe deficits are associated with a higher risk of seizures and epilepsy in most, but not all, circumstances.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Stroke incidence and mortality are similar among men and women, but because of differences in age distribution, 60% of stroke deaths occur in women. Incidence and mortality are also higher among African Americans than European Americans, with only about two-thirds of this difference accountable by differences in cardiovascular and socioeconomic risk factors. Age-adjusted mortality per 100,000 people is 61.5 for white men, 57.9 for white women, 88.5 for black men, and 76.1 for black women.31,32

In the United States, there are also regional differences in stroke incidence, which is highest in the southeastern United States (the “Stroke Belt”) and lowest in the southwestern and highly populated northeastern states.

Worldwide, there are large variations in incidence and mortality, with several countries of Eastern Europe having the highest rates. Among Asians, including Asian Americans, stroke incidence is high, especially in relation to relatively lower cardiovascular morbidity and mortality. This group also includes a higher proportion (about one-third) of hemorrhagic strokes relative to ischemic strokes. Also, large artery stenosis more commonly involves intracranial rather than extracranial vessels in both Asian Americans and African Americans than in European Americans.

In addition to age, hypertension (systolic and diastolic), smoking (for hemorrhage, as well as ischemia), and ethnic and regional differences, other risk factors for ischemic stroke include previous stroke, heart disease, and diabetes.31 Evidence for hypercholesterolemia as a risk factor is mixed, although recent studies suggest a benefit of statin-type cholesterol-lowering agents; these may have other effects in addition to lowering cholesterol, such as altering endothelial surfaces. Interestingly, low cholesterol has been associated with an increased incidence of hemorrhagic strokes, especially when combined with hypertension. Obesity is associated with several other risk factors, and any independent effect is likely to be small. Cancer, especially adenocarcinoma, predisposes to hypercoagulable states. Family history may elevate risk by approximately 50%, apart from other risk factors, and may be decisive in a minority of individuals with intracranial aneurysms and vascular malformations or inborn coagulation anomalies predisposing to bleeding or clotting. Risk of ischemic stroke also increases with blood levels of fibrinogen, homocysteine, and hematocrit, even within the normal range. Lack of exercise also increases risk of ischemic stroke, in addition to being linked to other risk factors, such as heart disease. Moderate alcohol use may be somewhat protective against ischemic stroke, but heavy use definitely increases the risk of hemorrhage. Among women, high-dose oral contraceptives increase risk of ischemia, especially when combined with smoking and older age; this combination is also associated with subarachnoid hemorrhage.31 Heart disease is a marker for atherosclerosis predisposing to stroke and is an independent risk factor for embolic disease. Atrial fibrillation is a widely recognized risk. Other heart conditions that are also significant include myocardial infarction, especially of the anterior wall; congestive heart failure; left ventricular hypertrophy; and patent foramen ovale.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Until the 1950s, studies of seizures after stroke were largely confined to necropsy studies.33 The advent of computed tomography (CT) in the 1970s and MRI a decade later markedly increased the accuracy of clinical diagnosis of stroke mechanisms, particularly with respect to distinguishing between ischemic and hemorrhagic infarcts. Nevertheless, comparison among different studies has been difficult because of different inclusion and exclusion criteria. Some have examined only ischemic stroke. Others have combined ischemic and hemorrhagic stroke, and some of these have excluded subarachnoid hemorrhage or vascular malformations.4 Fortunately, there have been several recent prospective studies of early,34–36 or both early and late,37,38 seizures that have followed large populations (more than 500 patients) for an adequate period of time to draw valid conclusions and have attempted to separately analyze clinically important subgroups. The smaller prospective or case-control studies,33,39–48 although less valid as sources of incidence data, still provide useful information about risk factors and clinical characteristics. Separate series of patients with intracerebral19,49–51 or subarachnoid52–57 hemorrhage or specific vascular malformations58–62 have provided important data about these subgroups.

Prospective analyses of combined groups have found lower overall seizure rates after ischemic stroke than hemorrhagic stroke. Bladin and colleagues,37 for example, found that 8.6% of 1,632 patients with ischemic stroke had seizures, versus 10.6% of 265 patients with hemorrhagic stroke. Because of higher mortality among patients with hemorrhagic stroke, survival analysis revealed an almost twofold increased risk of seizures in that group.

Among the patients in this study who had ischemic stroke, 4.8% had seizures within the first 2 weeks (early), including 3.4% within 24 hours (“onset”). For patients with hemorrhagic stroke, 7.9% had early seizures, with 6.0% at onset. Late seizures occurred with 3.8% of ischemic strokes and 2.6% of hemorrhagic strokes, and were more likely to recur than early seizures, a finding verifying nearly all earlier studies. In multivariate analysis, cortical location was the only risk factor for seizures after either type of stroke. Increased disability predicted seizures among the ischemic group. Hemorrhagic transformation conferred greater risk on univariate analysis, but a high likelihood of embolism did not, a finding confirmed by a large cohort in the National Institute of Neurological Disorders and Stroke’s Stroke Registry,63 despite conflicting results in earlier studies45,64 and in one large retrospective study.34

Lacunar infarction was associated with seizures in 2.6% of cases, although further analysis questioned this relationship. However, risk factors for lacunar disease, including hypertension, serum cholesterol, and left ventricular hypertrophy,65–67 have been associated with the development of seizures or epilepsy, even in those without overt stroke.

Kilpatrick and coworkers35 found early seizures in 24 (4%) of 604 patients with ischemic stroke (or 4.4%, excluding brain stem and cerebellar strokes, as did Bladin et al.37). All 24 patients with early seizures had cortical infarcts of the anterior circulation, although again embolism was not a risk factor. So and colleagues38 found 4.7% onset seizures and 6.2% early (1 week) seizures among those with infarction; initial late seizures occurred in an additional 5% of patients, and epilepsy in 3.3%. Early seizures were a significant risk factor for late seizures and epilepsy. The cumulative risk for initial late seizures was 7.4% by 5 years and 8.9% by 10 years.

A British prospective study of 675 patients with a first stroke, 545 of whom had infarction, found a 5-year actuarial risk of seizure of 11.5%.40 Such population-based studies have found seizure risk relative to the general population to be elevated by factors of 20 to 40. Early (2 weeks) seizures in a Danish cohort of 1,197 patients with ischemic infarct occurred in 4.2% of patients, 2.8% within 24 hours.36 Stroke severity was the only risk factor in a multivariate analysis.

Seizures have been attributed to transient ischemic attack (TIA) in 1–4% of patients.34,35 In some earlier studies,48,68 the possibility of seizures heralding TIA or stroke was advanced, although this relationship is tenuous.

Smaller studies examining occurrence of late seizures or epilepsy39,47 confirm the importance of large cortical infarcts and suggest a role for apparently preserved cerebral tissue within the infarcted area.39 Extensive white matter disease in combination with cortical infarction is also important.

No specific incidence figures have been published for seizures following border zone infarcts. One would expect that when these infarcts extend to the cortex, there would be risk similar to that of thrombotic lesions. However, the common electroencephalogram (EEG) occurrence of periodic lateralizing epileptiform discharges (PLEDs) after border zone infarcts69 argues that the frequency of seizures may be higher and that epilepsia partialis continua or other forms of partial status epilepticus might occur.

There are no data concerning seizures with less common stroke mechanisms, such as vasospasm as a result of migraine or vasculitis—only limited evidence linking seizures to specific cortical locations. An excess of seizures with strokes involving the anterior rather than posterior circulation may relate to a higher likelihood of cortical involvement. Within a given vascular territory, the probability of seizures or epilepsy may also relate to the intrinsic epileptogenicity of specific cortical regions. Limited evidence parallels that for brain tumors70 or unselected patients71 and suggests the highest probability associated with perirolandic cortex, followed by the temporal lobe, then prefrontal, parietal, and occipital regions.

Specific studies of intracerebral hemorrhages confirm that early seizures are common, occurring in 4.6–17.0%.50,51 All studies show lobar hemorrhages to have the highest rates, 15–24% or more.19,35,50,72 Most of these patients had hypertension. Among those with deep hemorrhages, the rate of early seizures ranges from 0% to 11%.19 The caudate and perhaps putamen are most often involved, and the thalamus least involved. As in infarctions, the majority of early seizures occur within the first day or two. About half of these patients had one or more seizures as the first symptom. Late seizures and epilepsy are much less common, even in those with early seizures. Between 2 and 5 years, only 6.5% of survivors had any seizures, in contrast to an observed cumulative incidence of 32%.19 Furthermore, life-table analysis in the same study suggested a cumulative prevalence of seizures to be 50% had all patients survived to 5 years.

Many patients with lobar hemorrhage in early studies may have had cerebral amyloid angiography, although specific data for seizure risk in this syndrome are not available. Nor are figures available specifically for hemorrhage caused by coagulopathies, but location probably plays an important role here also. In a retrospective study to evaluate the incidence of seizures in chronic subdural hematomas (some of which could result from coagulopathies), the rate of occurrence was less than 2%.73 After hemorrhage from dural arteriovenous fistulas, 5% of patients presented with a generalized seizure.18

In general, the incidence of epilepsy as a late sequela of stroke has been estimated at 3% to 10%, with those who have a late-onset seizure at higher risk (a second unprovoked, late-onset seizure by definition constituting epilepsy). Late seizures may occur earlier after hemorrhage than after infarction.45 The timing of the initial late seizure (after 1–2 weeks) does not predict later recurrence.74

Status epilepticus can occur, involving 31% of stroke patients with seizures in one large study. Status epilepticus was the initial seizure type in more than half of these patients.75

With respect to hemorrhagic infarcts due to vascular malformations, AVMs commonly (17– 40%) present with seizures.58,61,62 Presentation with a seizure alone is more common in younger patients. The cumulative risk of epilepsy in untreated patients is estimated at 1% per year, relative to a 2–4% risk of hemorrhage. Cavernous angiomas are commonly undiagnosed until a seizure occurs, with 40–70% presenting with seizures, usually in midlife; epilepsy is typical if the lesion is untreated.59,60 Venous angiomas rarely bleed and are usually incidental findings, but when hemorrhage occurs, seizures are common.

Subarachnoid hemorrhage presents with a seizure in a sizable minority (6.3–18.0%) of patients.55,56 In one study, thickness of the cisternal clot was the only predictive factor. Another 7% may have had presenting seizures, but loss of consciousness at the time of aneurysm rupture more commonly reflects temporary cessation of cerebral perfusion secondary to an acute rise in intracranial pressure. Acute symptomatic seizures may occur in 24–26%, and epilepsy can later develop in 25%, with a higher risk if there are neurologic sequelae and if acute seizures occurred.57,76 In a small retrospectively studied cohort with unruptured intracranial aneurysms, the overall risk of postoperative seizures in initially seizure-free patients was 15.7%.77

With cerebral venous thrombosis, seizures have been described in 40% of cases,28 but subsequent epilepsy appears rare, despite the high incidence of hemorrhage.

Acute symptomatic seizures are one of the hallmarks of hypertensive encephalopathy and related conditions (e.g., eclampsia, hyperperfusion syndrome), occurring in the majority. Later epilepsy is rare, however, paralleling the resolution of the often posterior white matter and cortical lesions typically seen on MRI.23,24

In the United States, migraine occurs in 18% of women and 6% of men.78 The prevalence of migraine with aura (which includes hemiplegic migraine) is lower, around 4%,79 and only a tiny fraction of patients ever experience the neuroimaging changes or persistence of symptoms for more than 1 week that defines migrainous infarction. No data are available on the frequency of seizures or epilepsy as a complication of this cause of stroke.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

No convincing evidence associates specific seizure types with stroke mechanisms, although location is clearly important. The semiology of late seizures usually parallels that of the early seizures,43 except that late seizures may be more likely to generalize.86

In one study of late seizures after infarction, simple partial seizures (most commonly with motor manifestations, with or without secondary generalization) accounted for 80% of the classifiable seizures, but it was not possible to determine the seizure type in half of the cases.39 Most of the remaining classifiable patients had what are considered to be generalized convulsions, although in the presence of a known focal lesion, often involving cortex, the likelihood of partial onset is very high, regardless of whether it is observed. Complex partial seizures, characterized by altered awareness with or without automatisms, would be expected, particularly with temporal and prefrontal lesions, but studies have not presented enough information to confirm this. Simple partial somatosensory or special sensory seizures are also likely to occur but can be difficult to diagnose unless the suspicion is high or a seizure later generalizes.

Because of involvement of posterior cerebral arteries, seizures resulting from posterior leukoencephalopathy due to hypertension, immunosuppressants, or eclampsia are often characterized by visual phenomena, including formed or unformed hallucinations or amaurosis, and seizures are often multiple.23

Status epilepticus

Any seizure type may present with status epilepticus (SE), and 8–17% of stroke patients with seizures have SE, often early in their course.75 Convulsive SE, although usually clinically obvious, can be subtle in a deeply comatose person after prolonged seizures and include only minor rhythmic face, limb, or eye movements.80 Nonconvulsive SE is difficult to diagnose and requires a high level of suspicion, especially in those who have not been known previously to have seizures.81–84 Diagnosis is easiest when there are recurrent, stereotyped complex partial seizures, characterized by unresponsiveness and automatisms and separated by incomplete recovery from the postictal state.

More difficult are patients in a continuous “twilight state,” classically associated with nonconvulsive generalized SE in those with idiopathic generalized epilepsy, but increasingly recognized as occurring de novo in elderly patients as a result of partial SE, often of frontal lobe origin.84 The diagnostic dilemma is particularly challenging in those with lesions of vascular or other origin that may in themselves impair cognition and awareness. If recovery does not occur as expected after a witnessed seizure, it is imperative to rule out nonconvulsive SE.85

Probably the most common form of simple partial SE after stroke is SE with focal motor manifestations. This can take the form of repeated brief tonic or clonic activity, or both, contralateral to the lesion, or sustained, somewhat irregularly repetitive movements, often confined to a very limited area such as the hand or the thumb, termed epilepsia partialis continua. This condition is notoriously difficult to treat and may persist for days or weeks. Newer drugs that act on the glutamate excitatory system, such as felbamate, may more effectively terminate this form of SE. Use of conventional antiepileptic drugs is still important, however, to prevent spread of the activity, which can involve wider areas of cortex and the corresponding hemibody, or produce complex partial or secondarily generalized seizures.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Neuroimaging abnormalities correspond primarily to the stroke itself, although after seizures (and particularly after status epilepticus), a variety of imaging changes sometimes persist for days or weeks.87 These usually affect cortex as well as white matter, and include

• hypodensity on CT
• T2 hyperintensity on MRI
• blurring of gray-white junction (localized edema)
• hyperintensity on diffusion-weighted imaging (in some cases)

These changes may be more confusing than enlightening in trying to determine whether seizures have occurred, but serial imaging correlated with the changing neurologic exam can be crucial to understanding the clinical process.

Perfusion imaging with MRI or single photon emission computerized tomography (SPECT) is also abnormal after stroke, showing hypoperfusion sometimes followed, after a week or more, by surrounding hyperperfusion. Perfusion images in status epilepticus, by contrast, show an increase ictally, usually a decrease postictally for minutes or longer, and then normalization (or return to the abnormal baseline in the case of a stroke). Similar changes can occur even after single seizures, but ictal SPECT in non–status epilepticus cases is seldom available outside the epilepsy monitoring unit.

EEG

Despite controversies about predictive value, the electroencephalogram (EEG) remains the fundamental investigation for patients with seizures. The main EEG manifestation after stroke is focal slowing. The development of a seizure focus may be accompanied by the appearance of epileptiform discharges such as sharp waves, spikes, or periodic lateralized epileptiform discharges (PLEDs). Studies suggest that interictal epileptiform discharges are less commonly seen in older than in younger patients with established epilepsy,88 but similar data are not available for acute seizures. On the other hand, sharp waves may occur even in studies of patients who do not have seizures. Well-defined spike foci may have higher predictive value than sharp waves, although detailed evidence is lacking. Most studies, however, suggest that PLEDs are a strong predictor of acute seizures.57,64,89,90 Focal slowing alone may also be somewhat predictive.47,86,91 EEG interpretation in the elderly must take into account that normal variants, particularly sharply contoured, alpha-frequency “wickets” in the temporal regions, are not indicators of a seizure tendency.

EEG manifestations of nonconvulsive status epilepticus require particular attention. The easiest pattern to diagnose, electrographically as well as clinically, is that of repeated individual seizures with incomplete recovery between episodes. More difficult are those that show continuous rhythmic activity, at times without well-defined spikes or sharp waves.82,83 This must be distinguished from other causes of more or less rhythmic slowing, especially those associated with metabolic disturbances. The triphasic wave pattern, classically and most commonly seen with hepatic encephalopathy but also associated with uremia, anoxia, and other conditions, is a particular source of confusion. A trial of intravenous benzodiazepines can sometimes clarify the situation if the EEG and patient improve, but one must keep in mind that the triphasic pattern usually disappears in sleep.

Long-term video-EEG monitoring is probably underused in elderly patients in general88 and in stroke patients in particular. This should be considered when any patient has relatively frequent events that could represent seizures or that have been treated as seizures with inadequate response. Concurrent monitoring of ECG and other physiologic parameters, such as respiratory effort and oxygen saturation, may sometimes suggest alternative diagnoses.

Laboratory tests

Laboratory evaluation is aimed at ruling out metabolic factors that could predispose to seizures.81 Serum chemistries, particularly sodium, calcium, magnesium, glucose, and renal indices, should be measured. Levels of potentially offending drugs, such as theophylline or the normeperidine metabolite of meperidine, can at times be obtained rapidly enough to be useful. Blood and urine toxic screens can be helpful in assessing the possibility of illicit drug use, particularly in younger patients with stroke and seizures. Cocaine is of particular importance.

Lumbar puncture is rarely a consideration in stroke patients, except when subarachnoid hemorrhage is considered and CT is negative for blood, or when the situation suggests that stroke could have resulted from an infectious vasculitis secondary to meningitis. In immunocompromised patients, for example, central nervous system aspergillosis is frequently accompanied by hemorrhage, as a result of fungal invasion through the vessel wall.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

The differential diagnosis of transient neurologic dysfunction is broad, and the elderly population that is at highest risk of stroke and transient ischemic attack (TIA) is also at risk of many conditions that can mimic seizures.3

Syncope

Syncope may not be benign in this population. Causes include92:

• hypovolemia (e.g., blood loss, diuretics)
• decreased arterial or venous tone (e.g., vasodilators, autonomic dysfunction)
• limited cardiac output (e.g., aortic stenosis, arrhythmias)
• inappropriate baroreceptor reflexes (e.g., emotional situations, Valsalva maneuver)

Upright posture at onset and a typical warning of lightheadedness, nausea, warmth, and fading vision and hearing are common but not universal, and stroke patients may have difficulty reporting these sensations. Cardiac arrhythmias, some potentially fatal, may lead to sudden loss of consciousness, even in the supine position. In these patients, palpitations may be noted if onset is not sudden or at other times.

A few myoclonic jerks commonly accompany syncope, and tonic stiffening (as well as more complex movements) may also occur, especially if the head is kept upright. The pathophysiology of such convulsive syncope is release of brain stem activity from cortical influence rather than an electrocortical seizure.

In addition, syncope can rarely occur as a vertebrobasilar TIA, especially when flow through one or both carotids is severely compromised.

Migraine

The episodic headache and other symptoms of migraine sometimes are preceded by an aura, 5 to 60 minutes of cortical or brain stem dysfunction.93 Migraine auras are distinguished from seizures by their more gradual, often visual, warning and longer duration. Associated symptoms include nausea or vomiting, photophobia, and phonophobia. Headache usually, but not always, follows. “Migraine equivalents” without headache are more common in the elderly and are occasional causes of TIA-like symptoms or of actual TIAs.15 Loss of consciousness is rare but may occur with so-called basilar migraine.

It must be recognized that migraine and epilepsy can coexist, that headaches often follow epileptic seizures, and that a migraine attack can, rarely, precipitate a seizure.93

Migraine is discussed more fully in Migraine and epilepsy.

Transient ischemic attacks (TIAs)

TIAs themselves can be confused with seizures, although they have characteristic symptoms and (if prolonged enough to persist to the time of evaluation) signs consistent with known vascular territories. They typically evolve over minutes and last minutes to hours.

Jackson was first to point out that seizures generally manifest “positive” symptoms, such as stiffening or shaking in the motor system or hallucinations in the special sensory modalities, whereas ischemic symptoms are usually “negative” (e.g., weakness, sensory loss). Exceptions to this rule include ischemic paresthesias, rare motor inhibitory seizures,94 and “limb-shaking” TIAs.95

"Limb-shaking TIAs" are rare manifestations of severe carotid stenosis. They can be distinguished from motor seizures mainly by

• their consistently postural character, usually occurring promptly on standing
• their involvement of arm, leg, or both, sparing facial muscles and cognition

On the other hand, rare seizure types, such as ictal amaurosis (total or hemianopic, not monocular) or aphasic status epilepticus,96 require EEG to be distinguished from TIAs.

Patients with cerebral amyloid angiopathy have been noted to have transient events for which the underlying pathophysiology has not been established; no evidence of microscopic bleeding, transient ischemia, or epilepsy has been discovered. The duration is more similar to that of TIAs than of the other potential etiologies.22

Movement disorders

Movement disorders can usually be readily distinguished from seizures because they are typically long-lasting and associated with preserved consciousness. Although usually bilateral, they may be unilateral after infarction, particularly infarction of the basal ganglia, thalamus, or subthalamus.

In patients with depressed mental status, toxic or metabolic processes may at times produce movement disorders, such as extrapyramidal reactions to neuroleptics or multifocal myoclonus in uremia. Although the multifocality is not typical of seizures, and the movements are not time-locked to epileptiform discharges on EEG, such discharges are often present and imply “cortical irritability” that may later be manifest as clear-cut seizures.

Asterixis, an abrupt, repetitive loss of muscle tone during maintenance of certain postures, often occurs in patients with depressed mental status due to hepatic or other encephalopathies. After cerebral or brain stem stroke, it can occur unilaterally, contralateral to the lesion. Its positional nature usually distinguishes it from motor seizures, although rare cases of epileptic asterixis have been reported.

Antiepileptic drugs, especially at toxic levels, also can produce involuntary movements, such as dystonia with phenytoin or tremor with valproate.

Sleep disorders

Sleep disorders may result in microsleeps or more prolonged sleep attacks due to any cause of hypersomnolence. The most common cause is disrupted sleep from obstructive sleep apnea, a condition which (like stroke) is common among patients with hypertension, atherosclerosis, and obesity. Furthermore, many thrombotic strokes, in particular, occur during sleep and are characterized by patients’ awakening with a new deficit.

The second most common medical reason for sleep deprivation leading to sleep attacks is the movement disorder termed periodic limb movements in sleep.97 These movements usually involve one or both lower limbs, with dorsiflexion of the ankle and flexion of the knee and hip, and are sustained for 1 to 2 seconds and repeated approximately every one-half minute. This condition is associated with restless legs syndrome, a need to walk around or otherwise move the legs, often in response to a crawling sensation felt when lying in bed or otherwise at rest.

Narcolepsy is a more dramatic but much less common cause of hypersomnolence, usually associated with symptoms of hypnagogic or hypnopompic hallucinations, sleep paralysis, and especially cataplexy.97 Onset is rare after early adulthood, although symptomatic cases related to brain stem trauma, demyelination, and, rarely, infarction have been reported. Although microsleeps may occur without warning, more prolonged sleep attacks are usually preceded by a subjective feeling of sleepiness. Unlike in complex partial seizures, the eyes are usually closed, and the patient may be awakened with stimulation.

Parasomnias can be difficult to distinguish from nocturnal seizures. The classic parasomnias of slow-wave sleep, sleepwalking, and night terrors are conditions of childhood, although the former sometimes persists into adulthood. They are not associated with stroke. In the population at risk for stroke, nocturnal wandering is more likely to occur after a complex partial seizure, and patients usually return to normal awareness rapidly, if stimulated.

A parasomnia of rapid eye movement (REM) sleep, REM behavior disorder, by contrast, typically begins late in life and may be associated with extrapyramidal syndromes such as Parkinson’s disease. Cases in patients with stroke may be coincidental, given the typical ages for both disorders. These attacks consist of partial arousals from REM with a loss of the usual muscle atonia, resulting in “acting out” of dreams, often in a violent manner that may reflect defensive behavior prompted by a frightening dream.97 The timing of the spells later in the night, when REM periods are longer, can be a useful clue. Polysomnography with additional EEG electrodes may be necessary to distinguish this disorder from nocturnal partial seizures.

Sleep disorders are discussed more fully in Sleep disorders and epilepsy.

Toxic-metabolic disturbances

Altered behavior due to toxic-metabolic disturbances usually lasts much longer than changes due to seizures. The possibility of certain causes of encephalopathy (e.g., hyperglycemia, hypoglycemia, hyponatremia, hypocalcemia, hypomagnesemia) precipitating acute symptomatic seizures can further confuse the picture.

The EEG, although typically showing diffuse slowing, can, at times, display multifocal sharp waves or the triphasic wave pattern, which may be difficult to distinguish from the generalized sharp-slow complexes of nonconvulsive generalized SE.

These disturbances are discussed more fully in Metabolic disorders and seizures.

Psychogenic nonepileptic seizures

Distinguishing psychogenic nonepileptic seizures (NESs), also known as pseudoseizures or psychogenic seizures, from epileptic seizures is a major undertaking of epilepsy monitoring units. Evidence suggests that this phenomenon is most common in young adults, especially women, but there are few data on the frequency and manifestations in elderly patients, and it may be underdiagnosed.

Patients with a previous psychiatric history are likely to be at higher risk, as may be those with depression or other psychiatric complications of stroke, but data are unavailable.

In general, compared to epileptic seizures, psychogenic NESs display less stereotypy, longer duration, a more waxing and waning nature, and nonphysiologic progression.98 Eyes tend much more often to be closed during unresponsive periods. Environmental precipitants are more likely and injuries less likely, although there are many exceptions. Unlike epileptic seizures, NES do not arise from sleep, although they may arise from “pseudosleep,” and video-EEG monitoring may be required.

Increased intracranial pressure

Transient increases in intracranial pressure can result in temporary alteration in awareness or, less often, focal neurologic dysfunction. The classic situations are a posterior fossa mass or intermittent obstruction of ventricular flow by a third ventricular tumor, but acute hydrocephalus can occur in patients after subarachnoid hemorrhage99 or after ischemic or hemorrhagic stroke in the cerebellum.

Patients with cerebral edema as a result of hemispheric infarction are likely to show catastrophic focal deficits followed by progressive obtundation.

Headache is common in all of these scenarios, if the patient is alert and articulate enough to report it.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Of about 30 drugs approved in the United States for the treatment of epilepsy, fewer than a dozen are in widespread use, including several developed and approved in the 1990s.100 There are few comparative studies, and those do not suggest major differences in efficacy. There is wider variation with respect to common adverse effects, available routes of administration, recommended dosing interval, interactions, and cost. These differences may be of particular importance for stroke patients.

The first step in treatment is to verify whether the episode was a seizure, as opposed to another type of transient event. (See Differential diagnosis of possible seizures in stroke patients.) Once that condition is satisfied, the decision to treat depends on the likelihood and potential morbidity of another seizure versus risks of treatment. In reported studies, relatively few patients have multiple acute seizures, but the fact that most such patients are given AEDs may account for this.

Although there are no data on the efficacy of treatment of acute seizures specifically in the setting of stroke, it may be reasonable to extrapolate from the widely cited study by Temkin and colleagues of patients with moderate and severe head trauma.101 In these patients, phenytoin was effective in preventing seizures within the first week, but it did not decrease the incidence of a first late seizure in patients followed for approximately 1 year.

Potential morbidity of acute post-stroke seizures includes increase in blood flow to an already edematous cerebrum, elevation of blood pressure, and danger of aspiration. Although seizures and status epilepticus are uncommon causes for deterioration,34,43 cases have been reported that involve permanent worsening after a seizure, despite lack of evidence of any additional stroke.102

On balance, it is reasonable to treat for a limited period any patient with a stroke (especially a large stroke) who has an acute seizure without an obvious toxic or metabolic precipitant. The duration of such treatment should be at least a week, and perhaps a month or longer.

Of patients with a single late seizure, the majority, although not all, go on to develop epilepsy. Treatment for these patients is justified for a longer period, perhaps for 1 to 2 years.

When epilepsy has developed (i.e., after two late seizures), treatment lasting at least 2 years, as in other cases of epilepsy, is indicated.

The use of EEG findings in deciding when to stop treatment has been questioned, although unequivocal epileptiform discharges and periodic lateralized epileptiform discharges (PLEDs) in the acute or subacute setting would argue for continued treatment. A history of status epilepticus of any type would also suggest longer treatment duration, because, in adults (unlike in children) the occurrence of status epilepticus as the first seizure carries a higher risk of seizure recurrence.6

One potential consideration concerns whether many AEDs, including phenytoin, phenobarbital, and benzodiazepines, perhaps by virtue of their ability to dampen sustained repetitive neuronal firing, may inhibit recovery from stroke.103 There is moderate laboratory and sparse clinical evidence that this is true. Because of the very real risk of morbidity posed by seizures in many situations, this possibility should not argue against treatment after a seizure has occurred, but it may be a consideration in cases in which prophylaxis is considered (e.g., large hemispheric lesions with edema) and may affect AED selection when there is more information available.

In subarachnoid hemorrhage, most seizures occur with rerupture of the aneurysm.53 Currently, no data are available to specifically justify prophylactic anticonvulsant agents in the presentation of a ruptured subarachnoid hemorrhage, but awareness of the morbidity risk of a seizure in this setting and the extrapolation of the data for head trauma101 would favor treatment.

In lobar hemorrhages, owing to the prevalence of generalized seizures, one can argue that prophylaxis is justified.19,35,49,50 Also, the theoretical risk of impeding recovery from infarction would not apply.

In cerebral venous thrombosis, prophylactic administration of AEDs is not justified if it has not presented with a seizure.

The choice of AEDs depends on potential routes of administration, interactions with other medications, and specific metabolic conditions, such as renal or hepatic impairment. Please visit the pages to the right for more information.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

In the inpatient setting, typically some or all of the loading dose is given parenterally. Although the familiar “gram of phenytoin” is adequate for loading in a patient who has had a single seizure, in treating convulsive status epilepticus, the target level should be in the range of 20–25 mg/liter, and so a loading dose of 18–20 mg/kg (keeping in mind that volume of distribution in adults is 0.8 mg/liter) should be given at the maximal rate of 50 mg per minute of phenytoin or 150 mg per minute of fosphenytoin (in phenytoin equivalents).101 Because of the possibility of decreases in pulse rate and blood pressure, cardiovascular monitoring is mandatory, sometimes necessitating a slower rate of infusion, administration of fluids, or, less commonly, pressors. Monitoring of vital signs is particularly important in stroke patients, who are usually elderly and often have cardiac disease.

Because of the slow absorption of phenytoin 100-mg or 30-mg extended-release capsules, oral loading is affected by metabolism and the dose to obtain a given peak level must be higher, approximately 1 mg/kg for each desired 1 mg/liter rise in level.

Peak oral level is reached more quickly if the 50-mg chewable tablet is used. This preparation, which contains the acid form rather than the sodium salt, has a slightly higher amount of phenytoin than does the equivalent dose of phenytoin sodium capsules.

The 125 mg/5 mL suspension also contains the acid form. It may be convenient to use in patients receiving tube feedings. Unless this preparation is vigorously shaken, however, the phenytoin may precipitate in the bottom of the bottle, yielding doses that are lower (if from the full bottle) or higher (if from the bottom of the bottle) than intended.

Important interactions with other drugs follow from two characteristics of phenytoin:

• It is highly protein bound, so that mutual displacement from binding sites occurs with several other drugs, most notably aspirin.
• It is a potent inducer of the P-450 mixed-function oxidase hepatic enzyme system responsible for the metabolism of many important drugs. (In stroke patients, the most important of these drugs is warfarin.) When phenytoin is added to these drugs, their doses typically must be increased if the therapeutic effect is to remain constant. Careful monitoring is needed of levels, therapeutic effects (e.g., prothrombin time), or both. This interaction takes several days to develop fully. Conversely, when phenytoin is withdrawn, the warfarin dose must be reduced and prothrombin times followed closely. Other drugs frequently used in stroke patients whose metabolism is induced by phenytoin (or other enzyme-inducing AEDs, including phenobarbital and carbamazepine) include digoxin, many anti-arrhythmic agents, and beta-blockers.

The situation most commonly necessitating phenytoin discontinuation is the development of a rash, which occurs in 5–10% of patients, or less common idiosyncratic reactions, such as fever, lymphadenopathy, hepatic dysfunction, or a combination of these. Although the rash may resolve even without discontinuation, most clinicians elect not to continue treatment. One must recognize, however, that in elderly patients, who often take a number of medications, many other drugs, particularly antibiotics, can also cause rash.

There is no evidence that sudden discontinuation of phenytoin causes withdrawal seizures, but if it is needed for seizure control, prudence dictates coverage with adequate doses of an alternative AED when phenytoin is withdrawn. The two most commonly used alternatives, phenobarbital and carbamazepine, may cause cross-reactivity allergic reactions as often as 20% of the time. If the reaction is not severe, this risk may be reasonable.

Dose-related side effects primarily include dizziness and ataxia; chronic effects include gum hyperplasia (more common in children), and osteopenia, mediated largely but not completely through interference with vitamin D metabolism. This is a particular concern in older women, who should be considered for bone density screening, vitamin D supplementation, and other medical therapy if long-term treatment is anticipated.

With respect to cognitive effects, no major differences have been found among phenytoin, carbamazepine, and valproate.104,105 (Phenobarbital is likely to have more detrimental effects, on average.) Further studies are needed to establish whether newer AEDs have less effect on cognition than phenytoin and the other older AEDs.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Like phenytoin and carbamazepine, phenobarbital is a potent inducer of the hepatic P-450 enzyme system and has similar effects on the metabolism of warfarin and other drugs and on bone density.

Dose-related effects include sedation, depression, and cognitive slowing, as well as dizziness and ataxia. On average, phenobarbital is likely to have more detrimental cognitive effects than phenytoin, carbamazepine, and valproate.104,105

Chronic effects on connective tissue, such as frozen shoulder, have also been reported.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

• bradyarrhythmias due to slowed conduction at the atrioventricular node (especially at high levels)
• hyponatremia as a result of renal insensitivity to antidiuretic hormone
• drug interactions similar to those described for phenytoin and phenobarbital. Carbamazepine metabolism is sensitive to many other enzyme inducers and inhibitors. Among the enzyme inhibitors, which can produce major carbamazepine toxicity, are such commonly used drugs as erythromycin, cimetidine, and verapamil.
• dose-related adverse effects, most commonly dizziness and diplopia

With respect to cognitive effects, no major differences have been found among carbamazepine, phenytoin, and valproate.104,105 (Phenobarbital is likely to have more detrimental effects, on average.) Further studies are needed to establish whether newer AEDs have less effect on cognition than carbamazepine and the other older AEDs.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Valproate or the dimeric form, divalproex, offers a useful alternative to phenytoin, phenobarbital, and carbamazepine, especially with the intravenous formulation that became available in the mid-1990s. It is effective against tonic-clonic seizures (including secondarily generalized seizures), as well as absence, myoclonic, and simple and complex partial seizures. Carbamazepine may have slight advantages for patients whose partial seizures do not secondarily generalize.

Because of valproate's short half-life (12–16 hours without concomitant administration of P-450–inducing drugs, 5–10 hours with such administration), a steady state is reached rapidly at the maintenance dose of 15–30 mg/kg. Higher loading doses may also be used, although gastrointestinal upset can occur. A liquid form is also available, at 250 mg/5 mL.

The enteric-coated divalproex preparation, although less likely to produce gastrointestinal upset, has delayed absorption, resulting in peak levels 4–6 hours after administration.

The intravenous formulation offers an option when gastrointestinal administration is unavailable, such as postoperatively or with impaired swallowing and no nasogastric access. It also has been used successfully off label in treating status epilepticus, often at administration rates much faster than the recommended 20 mg/kg per hour.

One advantage of valproate is its lack of cross-reactivity with phenytoin, phenobarbital, and carbamazepine. Rashes and other overt allergic reactions are uncommon. Although idiosyncratic hepatic dysfunction and pancreatitis are the most feared adverse reactions, these are extremely rare after infancy in the absence of pre-existing organ dysfunction.

A potentially more important risk in an ill, elderly patient is the possibility of thrombocytopenia or thrombocytopathy. Although idiosyncratic, this is more common at high doses and levels. Bleeding time is not always abnormal, and aspirin can potentiate this effect. There have been no studies of whether this antiplatelet effect can be beneficial in patients with vascular disease.

Aspirin also potentiates the therapeutic effects of valproate by displacing it from binding sites, thereby elevating free levels. The total level may be unchanged or even decline slightly because of increased free drug as a substrate for metabolism.

Among other potential adverse effects, tremor is most common at high doses and levels. Weight gain with chronic use occurs in about 30% of patients.

With respect to cognitive effects, no major differences have been found among valproate, phenytoin, and carbamazepine.104,105 (Phenobarbital is likely to have more detrimental effects, on average.) Further studies are needed to establish whether newer AEDs have less effect on cognition than valproate and the other older AEDs.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

For refractory tonic-clonic SE, intravenous propofol, midazolam, or pentobarbital have been used.106 Propofol and midazolam are preferable to pentobarbital in most stroke patients, who are more prone to hypotensive effects because of age and comorbidity. Drug-induced coma with these agents is also a consideration in refractory complex partial SE.

Eclampsia and other hypertensive conditions

For acute symptomatic seizures due to eclampsia, phenytoin and benzodiazepines may have a role, but recent studies suggest that intravenous magnesium is the mainstay of treatment.25,26 One regimen is a 4-g load, followed by continuous infusion of 2–4 g per hour, to maintain a level of 4–8 mg/dL without losing deep tendon reflexes and muscle strength.

Whether this regimen should also be used in hypertensive or immunosuppressant-related posterior leukoencephalopathy is not known. When hypertension is clearly a causal factor, rapid control of blood pressure using labetalol or nitroprusside is recommended.

Anticoagulation

Stroke treatments sometimes need to be modified because of the coexistence of seizures or the use of AEDs. The enzyme-inducing AEDs (phenytoin, carbamazepine, phenobarbital) produce major increases in warfarin metabolism, so that warfarin doses must be adjusted when these AEDs are initiated or withdrawn, or when major dose changes are made.

Furthermore, warfarin may be contraindicated if seizures are not completely controlled and sometimes result in falls. This is a concern mainly in patients with atrial fibrillation, the best-supported indication for anticoagulation. Alternative treatments, such as adjusted subcutaneous heparin or low-molecular-weight heparin preparations, are likely to pose similar risk of serious bleeding in those prone to falls or other trauma. Antiplatelet agents have lower risk but also lower efficacy in stroke prevention for those with atrial fibrillation. Antiplatelet agents must be used with caution in patients on valproate.

Surgery

For those undergoing surgery, including endarterectomies, aneurysm clipping, or resection of a vascular malformation, postoperative changes in absorption and metabolism of AEDs must be considered. Medications with intravenous formulations do not pose a problem, as doses are equivalent to the oral forms. Medications without parenteral forms generally can be given via a nasogastric tube, but only if the gastrointestinal tract is functional. Pharmacies can prepare suppositories for rectal administration in some cases, as for carbamazepine.

An alternative is temporary administration of an alternative drug intravenously. For example, 1 mg of lorazepam two or three times daily can provide adequate antiseizure coverage in many cases for 1 or 2 days. If longer parenteral administration is required, phenytoin is a reasonable alternative.

Postoperative metabolic changes are another consideration. Phenytoin levels fall after general anesthesia, and carefully following levels and giving boluses as needed can prevent seizures in this setting. Carbamazepine levels may fall initially, either because oral doses are missed or because absorption is decreased, but on the next day the levels may sometimes rise significantly. Clinical toxicity often does not occur, however, because the increase may be due to diminished conversion to the somewhat more toxic epoxide metabolite.

Folate and homocysteine levels

Another potential issue is the recent observation that many AEDs not only decrease folic acid levels, but also increase levels of homocysteine, a recently identified risk factor for stroke.107 A surprising finding was that this effect was not limited to the older enzyme-inducing AEDs, which that are known to increase folate metabolism, although the numbers of patients taking newer medications were small. The effects were larger in older individuals and in men. Although most patients had folate and homocysteine levels in the normal range, there may still be implications for stroke risk.

Vasculitis

A final consideration in modifying stroke treatment when patients have seizures concerns the unusual condition of vasculitis. Hepatic enzymes metabolize the immunosuppressant drugs used to treat these conditions, including cyclosporine A and corticosteroids, and doses may need to be increased when inducing AEDs are added. Furthermore, cyclosporine A can lower the seizure threshold and must be used with caution in seizure patients.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Most studies have not shown an effect of seizures per se on stroke morbidity or mortality,35,37 although this is confounded (especially in hemorrhagic stroke) by mortality in the most severely affected patients before development of seizures.19 There are rare cases of deficits seeming to worsen permanently after a seizure or series of seizures.102 The occurrence of seizures in 15% of stroke rehabilitation patients did not affect functional outcome.108

The prognosis of epilepsy caused by stroke is not clearly different from epilepsy due to other causes, although as a group, elderly patients tend to have better seizure control than younger patients.3 Most series that address this issue indicate that seizures are readily controlled with antiepileptic drugs (AEDs).34,35,84 Whether control differs for ischemic or hemorrhagic stroke is unclear.

Post-stroke epilepsy usually responds well to adequate doses of a single agent. If seizures are completely controlled, AED withdrawal can be considered after 2 years. Risk of recurrence is probably higher among patients with structural lesions and an abnormal examination than among those without, particularly if there were also acute symptomatic seizures.109,110

The potential consequences of a recurrent seizure are highly variable, depending on activities such as driving or medications such as anticoagulants. Just as in deciding whether to start AEDs, the decision to withdraw them must be individualized.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

1. Jackson JH. On the Scientific and Empirical Investigation of the Epilepsies. In J Taylor (ed), Selected Writings of John Hughlings Jackson. London: Hodder and Stoughton, 1931;233. Referenced in: Lesser RP, Luders H, Dinner DS, Morris HH. Epileptic seizures due to thrombotic and embolic cerebrovascular disease in older patients. Epilepsia 1985;26:622–630.

2. Gowers WR. Epilepsy and Other Chronic Convulsive Disorders. New York: Dover, 1964;106. Referenced in: Lesser RP, Luders H, Dinner DS, Morris HH. Epileptic seizures due to thrombotic and embolic cerebrovascular disease in older patients. Epilepsia 1985;26:622–630.

3. Bromfield EB. Seizure Disorders in the Elderly. In SC Schachter, D Schomer (eds), The Comprehensive Evaluation and Treatment of Epilepsy: a Practical Guide. San Diego: Academic, 1997;233–254.

4. Ettinger AE. Structural causes of epilepsy. Neurol Clin 1994;12:41–56.

5. Thomas SV, Pradeep KS, Rajmohan SJ. First ever seizures in the elderly: a seven-year follow-up study. Seizure 1997;6:107–110.

6. Hesdorffer DC, Lograscino G, Cascino G, et al. Risk of unprovoked seizure after acute symptomatic seizure or status epilepticus. Ann Neurol 1998;44:908–912.

7. Sigurdsson AP, Feldmann E. Stroke. In MA Samuels (ed), Hospitalist Neurology. Boston: Butterworth–Heinemann, 1999;133–158.

8. Suzer T, Coskun E, Demir S, Tahta K. Lipid peroxidation and glutathione levels after cortical injection of ferric chloride in rats: effects of trimetazidine and deferoxamine. Res Exp Med 2000;199:223–229.

9. Willmore LJ, Sypert GW, Munson JB. Recurrent seizures induced by cortical iron injection: a model of posttraumatic epilepsy. Ann Neurol 1978;4:329–336.

10. Nag S, Robertson DM, Dinsdale HB. Cerebral cortical changes in acute experimental hypertension: an ultra- structural study. Lab Invest 1977;36:150–161.

11. Oppenheimer BS, Fishberg AM, Hypertensive encephalopathy. Arch Intern Med 1928;41:264.

12. Caplan LR. Basic Pathology, Anatomy, and Pathophysiology of Stroke. In LR Caplan (ed), Stroke: A Clinical Approach. Boston: Butterworth–Heinemann, 1993;23–66.

13. Caplan LR. Brain Embolism. In LR Caplan (ed), Stroke: A Clinical Approach. Boston: Butterworth–Heinemann, 1993;349–375.

14. Wijdicks EF, Parisi JE, Sharbrough FW. Prognostic value of myoclonus status in survivors of cardiac arrest. Ann Neurol 1994;35:239–243.

15. Caplan LR. Nonatherosclerotic Ischemia. In LR Caplan (ed), Stroke: A Clinical Approach. Boston: Butterworth–Heinemann, 1993;319–348.

16. O’Brien TJ, Kazemi J, Cascino GD. Localization-Related Epilepsies Due to Specific Lesions. In J Engel Jr, TA Pedley (eds), Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott–Raven, 1997;2433–2445.

17. Robinson JR, Awad IA, Little JR. Natural history of the cavernous angioma. J Neurosurg 1991;75:709–714.

18. Daffau H, Lopes M, Janosevic V, et al. Early rebleeding from intracranial dural arteriovenous fistulas: report of 20 cases and review of the literature. J Neurosurg 1999;90:78–84.

19. Faught E, Peters D, Bartolucci A, et al. Seizures after primary intracerebral hemorrhage. Neurology 1989;39:1089–1093.

20. Coria F, Rubio I. Cerebral amyloid angiopathies. Neuropathol Appl Neurobiol 1996;22:216–227.

21. Gilbert JJ, Vinters HV. Cerebral amyloid angiopathy; incidence and complications in the aging brain. Cerebral hemorrhage. Stroke 1983;14:915–923.

22. Greenberg SM, Vonsattel JP, Stakes JW, et al. The clinical spectrum of cerebral amyloid angiopathy. Neurology 1993;43:2073–2079.

23. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494–500.

24. Schwartz RB, Jones KM, Kalina P, et al. Hypertensive encephalopathy: findings on CT, MR imaging, and SPECT imaging in 14 cases. AJR Am J Roentgenol 1992;159:279–383.

25. Cunningham FG, MacDonald PC, Gant NF, et al. Hypertensive Disorders in Pregnancy. In: Williams Obstetrics (20th ed). Stamford, CT: Appleton & Lange, 1997;693–744.

26. Chien PF, Khan KS, Arnott N. Magnesium sulphate in the treatment of eclampsia and pre-eclampsia: an overview of the evidence from randomised trials. J Obstet Gynaecol 1996;103:1085–1091

27. Reigel MM, Hollier LH, Sundt T, et al. Cerebral hyperperfusion syndrome: a cause of neurologic dys- function after carotid endarterectomy. J Vasc Surg 1987;5:628–634.

28. Bousser MG, Barnett HJ. Cerebral Venous Thrombosis. In Barnett HJ, Mohr JP, Stein BM, Yatsu FM (eds), Stroke (3rd ed). New York: Churchill Livingstone, 1998;623–648.

29. Partziguian T, Camerlingo M, Castro L, et al. Cerebral venous thrombosis in young adults: experience in a stroke unit, 1988–1994. J Neurol Sci 1996;17:419–422.

30. Preter M, Tzourio C, Ameri A, Bousser MG. Long- term prognosis in cerebral venous thrombosis: follow- up of 77 patients. Stroke 1996;27:243–246.

31. Wolf, PA. Epidemiology and Stroke Risk Factors. In MA Samuels, S Feske (eds), Office Practice of Neurology. New York: Churchill Livingstone, 1996;224–236.

32. http://www.americanheart.org/Heart_and_Stroke_A_Z_Guide/strokes.html. Accessed 2001.

33. Richardson EP, Dodge PR. Epilepsy in cerebral vascular disease. A study of the incidence and nature of seizures in 104 consecutive autopsy-proven cases of cerebral infarction and hemorrhage. Epilepsia 1954;3:49–65.

34. Giroud M, Gras P, Fayolle H, et al. Early seizures after acute stroke: a study of 1640 cases. Epilepsia 1994;35:959–964.

35. Kilpatrick CJ, Davis SM, Tress BM, et al. Epileptic seizures in acute stroke. Arch Neurol 1990;47:157–160. <

36. Reith J, Jorgensen HS, Nakayama H, et al. Seizures in acute stroke: predictors and prognostic significance. The Copenhagen Stroke Study. Stroke 1997;28:1585–1589.

37. Bladin CF, Alexandrov AV, Bellavance A, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol 2000;57:1617–1622.

38. So EL, Annegers JF, Hauser WA, et al. Population- based study of seizure disorders after cerebral infarction. Neurology 1996;42:350–355.

39. Awada, AM, Omojola MF, Obeid T. Late epileptic seizures after cerebral infarction, Acta Neurol Scand 1999;99:265–268.

40. Burn J, Dennis M, Bamford J, et al. Epileptic seizures after a first stroke: the Oxfordshire Community Stroke Project. BMJ 1997;315:1582–1587.

41. Cocito L, Favale E, Reni L. Epileptic seizures in cerebral arterial occlusive disease. Stroke 1982;13:189–195.

42. Daniele O, Mattaliano A, Tassinari CA, Natale E. Epileptic seizures and cerebrovascular disease. Acta Neurol Scand 1989;80:17–22.

43. Kilpatrick CJ, Davis SM, Hopper JL, Rossiter SC. Early seizures after stroke: risk of late seizures. Arch Neurol 1992;49:509–511.

44. Lancman ME, Golimstok A, Norscini J, et al. Risk factors for developing seizures after a stroke. Epilepsia 1994;34:141–143.

45. Lesser RP, Luders H, Dinner DS, Morris HH. Epileptic seizures due to thrombotic and embolic cerebrovascular disease in older patients. Epilepsia 1985;26:622–630.

46. Louis S, McDowell F. Epileptic seizures in non-embolic cerebral infarction. Arch Neurol 1967;17:414–418.

47. Olsen TS, Hagenhaven H, Thage O. Epilepsy after stroke. Neurology 1987;37:1209–1212.

48. Shinton RA, Gill JS, Melnick AK. The frequency, characteristics, and prognosis of epileptic seizures at the onset of stroke. J Neurol Neurosurg Psychiatry 1988;51:273–276.

49. Weisberg LA, Shamsnia M, Elliott D. Seizures caused by nontraumatic parenchymal brain hemorrhages. Neurology 1991;41:1197–1199.

50. Berger AR, Lipton RB, Lesser ML, et al. Early seizures following intracerebral hemorrhage: Implications for therapy. Neurology 1988;38:1363–1365.

51. Sung CY, Chu NS. Epileptic seizures in intracerebral hemorrhage. J Neurol Neurosurg Psychiatry 1989;52:1273–1276.

52. Butzkueven H, Evans AH, Pitman A, et al. Onset seizures independently predict poor outcome after subarachnoid hemorrhage. Neurology 2000;55:1315–1320.

53. Hasan D, Schonck RS, Avezaat CJ, et al. Epileptic seizures after subarachnoid hemorrhage. Ann Neurol 1993;33:286–291.

54. Olafsson E, Gudmundsson G, Hauser WA. Risk of epilepsy in long-term survivors of surgery for aneurysmal subarachnoid hemorrhage: a population-based study in Iceland. Epilepsia 2000;41:1201–1205.

55. Pinto AN, Canhao P, Ferro JM. Seizures at the onset of subarachnoid haemorrhage. J Neurol 1996;243:161–164.

56. Rhoney DH, Tipps LB, Murry KR, et al. Anticonvulsant prophylaxis and timing of seizures after aneurysmal subarachnoid hemorrhage. Neurology 2000;55:258–265.

57. Sundaram MB, Chow F. Seizures associated with spontaneous subarachnoid hemorrhage. Can J Neurol Sci 1986;13:229–231.

58. Del Curling O, Kelly DL, Elster AD, Craven TE. An analysis of the natural history of cavernous angiomas. J Neurosurg 1991;75:702–708.

59. Farmer JP, Cosgrove GR, Villemure JG, et al. Intracerebral cavernous angiomas. Neurology 1988;38:1699–1704.

60. Fults D, Kelly DL. Natural history of arteriovenous malformations of the brain: a clinical study. Neurosurgery 1984;15:658–662.

61. Hofmeister C, Stapf C, Hartmann A, et al. Demographic, morphological, and clinical characteristics of 1289 patients with brain arteriovenous malformations. Stroke 2000;31:1307–1310.

62. Piepgras DG, Sundt TM, Ragoowansi AT, Stevens L. Seizure outcome in patients with surgically treated cerebral arteriovenous malformations. J Neurosurg 1991;78:5–11.

63. Kittner SJ, Sharkness CM, Price TR, et al. Infarcts with a cardiac source of embolism in the NINCDS Stroke Data Bank: historical features. Neurology 1990;40:281–284.

64. Holmes GL. The electroencephalogram as a predictor of seizures following cerebral infarction. Clin Electroencephalogr 1980;11:83–86.

65. Li X, Breteler MM, deBruyne MC, et al. Vascular determinants of epilepsy: the Rotterdam study. Epilepsia 1997;38:1216–1220.

66. Ng SK, Hauser WA, Brust, JC, et al. Hypertension and the risk of new-onset unprovoked seizures. Neurology 1993;43:425–428.

67. Hesdorffer DC, Hauser WA, Annegers JF, Rocca WA. Severe, uncontrolled hypertension and adult-onset seizures: a case-control study in Rochester, Minnesota. Epilepsia 1996;37:736–741.

68. Cocito L, Favale E, Reni L. The frequency, characteristics, and prognosis of epileptic seizures at the onset of stroke. J Neurol Neurosurg Psychiatry 1989;52:292.

69. Franck G. Borderzone (“watershed”) cerebral ischemia. Electroencephalogr Clin Neurophysiol 1982;35[Suppl]:297–306.

70. Ketz E. Brain Tumors and Epilepsy. In PJ Vinken, GW Bruyn (eds), Handbook of Clinical Neurology. Amsterdam: North Holland Publishing, 1974;254–269.

71. Manford M, Hart YM, Sander JW, Shorvon SD. National general practice study of epilepsy (NGPSE): partial seizure patterns in a general population. Neurology 1992;42:1911–1917.

72. Sing CY, Chu NS. Epileptic seizures in intracerebral haemorrhage. J Neurol Neurosurg Psychiatry 1989;52: 1273–1276.

73. Ohno K, Maehara T, Ichimura K, et al. Low incidence of seizures in patients with chronic subdural haematoma. J Neurol Neurosurg Psychiatry 1993;56:1231–1233.

74. Asconape JJ, Penry JK. Poststroke seizures in the elderly. Clin Geriatr Med 1991;7:483–492.

75. Rumbach L, Sablot D, Berger E, et al. Status epilepticus in stroke: report on a hospital-based cohort. Neurology 2000;54:350–354.

76. Hart RG, Byer JA, Slaughter JR, et al. Occurrence and implications of seizures in subarachnoid hemorrhage due to ruptured intracranial aneurysms. Neurosurgery 1981;8:417–421.

77. Rabinowicz AL, Ginsburg DL, DeGiorgio CM, et al. Unruptured intracranial aneurysms: seizures and anti- epileptic drug treatment following surgery. J Neurosurg 1991;75:371–373.

78. Adams HP Jr, Putman SF, Corbett JJ, et al. Amaurosis fugax; the results of arteriography in 59 patients. Stroke 1983;14:742–744.

79. Rasmussen BK, Olesen J. Migraine with aura and migraine without aura; an epidemiological study. Cephalalgia 1992;12:221–228.

80. Drislane FW, Schomer DL. Clinical implications of generalized electrographic status epilepticus. Epilepsy Res 1994; 19:111–122.

81. Bromfield EB. Seizures. In MA Samuels (ed), Hospitalist Neurology. Boston: Butterworth–Heinemann, 1999;79–108.

82. Jordan KG. Continuous EEG and evoked potential monitoring in the neuroscience intensive care unit. J Clin Neurophysiol 1993;10:445–475.

83. Privitera M, Hoffman M, Moore JL, Jester D. EEG detection of non–tonic-clonic status epilepticus in patients with altered consciousness. Epilepsy Research 1994;18:155–166.

84. Tomson T, Svanborg E, Wedlund JE. Nonconvulsive status epilepticus: high incidence of complex partial status. Epilepsia 1986;27:276–285.

85. Fagan KJ, Lee SI. Prolonged confusion following convulsions due to generalized nonconvulsive status epilepticus. Neurology 1990;40:1689–1694.

86. Gupta SR, Neheedy MH, Elias D, et al. Postinfarction seizures: a clinical study. Stroke 1988;19:1477–1481.

87. Yaffe K, Ferriero D, Barkovich AJ, Rowley H. Reversible MRI abnormalities following seizures. Neurology 1995;45:104–108.

88. Drury I. Diagnostic Assessment of Seizures in the Elderly. In LJ Willmore (ed), Epilepsy in the Elderly. West Hartford, CT: American Epilepsy Society, 1998;17–28.

89. Charlin C, Tiberge M, Calvet U, et al. The clinical significance of periodic lateralized epileptiform discharges in acute ischemic stroke. J Stroke Cerebrovasc Dis 2000;9:298–302.

90. Pohlmann-Eden B, Hoch DB, Cochius JI, Chiappa KH. Periodic lateralized epileptiform discharges—a critical review. J Clin Neurophysiol 1996;13:519–530.

91. Hughes JR, Zialcita ML. EEG in the elderly: seizures vs. syncope. Clin Electroencephalogr 2000;31:131–137.

92. Linzer M, Grubb B, Ho S, et al. Cardiovascular causes of loss of consciousness in patients with presumed epilepsy. Am J Med 1994;96:146–154.

93. Ehrenberg BL. Unusual manifestations of migraine and “the borderland of epilepsy”—re-explored. Semin Neurol 1991;11:118–127.

94. Lee H, Lerner A. Transient inhibitory seizures mimicking crescendo TIAs. Neurology 1990;40:165–166.

95. Baquis GD, Pessin MP, Scott M. Limb shaking—a carotid TIA. Stroke 1985;16:444–448.

96. Grimes DA, Guberman A. De novo aphasic status epilepticus. Epilepsia 1997;38:945–949.

97. Labar DR. Sleep disorders and epilepsy: differential diagnosis. Semin Neurol 1991;11:128–134.

98. Devinsky O. Nonepileptic psychogenic seizures: quagmires of pathophysiology, diagnosis, and treatment. Epilepsia 1998;39:458–462.

99. Hasan D, Vermeulen M, Wijdicks EF, et al. Management problems in acute hydrocephalus after subarachnoid hemorrhage. Stroke 1989;20:747–753.

100. Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med 1996;334:168–175.

101. Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 1990;323:497–502.

102. Bougousslavsky J, Martin R, Regli F, et al. Persistent worsening of stroke sequelae after delayed seizures. Arch Neurol 1992;49:385–388.

103. Goldstein LB. Common drugs may influence motor recovery after stroke. The Sygen In Acute Stroke Study Investigators. Neurology 1995;45:865–871.

104. Dodrill CB, Troupin AS. Neuropsychological effects of carbamazepine and phenytoin; a reanalysis. Neurology 1991;41:141–143.

105. Meador KJ, Loring DW, Huh K, et al. Comparative cognitive effects of anticonvulsants. Neurology 1990;40:391–394.

106. Lowenstein DH, Alldredge BK. Current concepts: status epilepticus. N Engl J Med 1998;338:970–976.

107. Ali I, Khuder S, Pirzada N, et al. Folate and plasma homocysteine in patients on long term antiepileptic drug therapy. Epilepsia 2000;41[Suppl 41]:203(abst).

108. Paolucci S, Silvestri G, Lubich S, et al. Poststroke late seizures and their role in rehabilitation of inpatients. Epilepsia 1997;38:266–270.

109. Berges S, Moulin T, Berger E, et al. Seizures and epilepsy following stroke: recurrence factors. Eur Neurol 2000;43:3–8.

110. Annegers JF, Hauser WA, Elveback LR. Remission of seizures and relapse in patients with epilepsy. Epilepsia 1979;20:729–737.

Adapted from: Bromfield, EB, and Henderson GV. Seizures and cerebrovascular disease. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;269–289.
With permission from Elsevier (www.elsevier.com).

Reviewed April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.