Management of Seizures in the Emergency Department

EXECUTIVE SUMMARY

• A seizure is an episode of abnormal and excessive cortical electrical activity producing a sudden change in behavior, characterized by abnormal movement, sensory perception, or change in consciousness.
• Epilepsy is the clinical condition of recurrent, unprovoked seizures.
• Nonconvulsive status epilepticus presents as a persistent change (greater than 30 minutes) in behavior from the patient’s baseline, with absent or clinically subtle motor symptomatology.
• During or immediately after a seizure, evaluate the blood glucose using a point-of-care device since both hypoglycemia and hyperglycemia can trigger seizure activity.
• Laboratory and neuroimaging should be obtained for patients with a first-time seizure.
• Laboratory studies and neuroimaging in patients with a known seizure who present with a typical (for them) seizure and quickly recover back to baseline often are not necessary.
• Patients presenting with an active seizure should receive antiepileptic medications as quickly as possible because the longer the seizure continues, the more difficult it may be to achieve pharmacologic control.
• If seizures continue despite two doses of a benzodiazepine, administer a second-line agent, such as fosphenytoin or valproate.
• Seizures that continue despite treatment with benzodiazepine and a second-line anticonvulsant therapy — termed refractory status epilepticus — should be treated with an intravenous anesthetic agent, endotracheal intubation, and mechanical ventilation.

Seizures and status epilepticus are common neurologic emergencies accounting for 1% of all emergency department (ED) visits.¹ These potentially life-threatening presentations can be challenging for emergency clinicians and other healthcare providers to manage in the acute setting. Further complicating the diagnosis and evaluation is the confusing and continuously evolving terminology used to classify and define seizures.

While most seizures will be brief and self-limited, prolonged seizure activity and status epilepticus represent high morbidity and mortality presentations. Aggressive escalation with benzodiazepines, second-line therapies, and anesthetics will help mitigate pharmacologic resistance to antiepileptic agents seen with prolonged seizure duration.

If the patient arrives to the ED with active seizures, the initial focus is to support the cardiopulmonary systems and stop the seizures. After seizures have stopped and cardiopulmonary systems have been stabilized, the next step is to identify any potential secondary etiologies, such as vascular insults, infectious sequelae, metabolic derangements, toxins, head trauma, and malignancy, among others. A focused history and physical examination also may help differentiate seizures from other conditions that can mimic them, including convulsive syncope, cardiac dysrhythmias, and nonepileptic attacks.

This review aims to summarize the best available evidence on seizure evaluation, classification, and acute management.

Definitions and Classifications

A seizure is an episode of abnormal and excessive cortical electrical activity producing a sudden change in behavior, characterized by abnormal movement, sensory perception, or change in consciousness.² (See Table 1.) Depending on the area and extent of the brain involved, seizures may or may not have a motor component, characterized as convulsive or nonconvulsive, respectively. Seizures may start with focal or generalized motor activity, visual or other sensory symptoms, altered mental status, or autonomic disturbances.^3-5 Alternatively, seizures may be subclinical and not clinically apparent.⁶

The term convulsion refers to the motor manifestation of the abnormal cortical activity and can be further characterized as tonic, clonic, tonic-clonic, or myoclonic based on the description of the motor activity. The tonic phase involves sustained muscle contractions that result in the stiffening of the extremities and body.^6-8 Clonic refers to repetitive and rhythmic muscle jerks.^6-8 Therefore, tonic-clonic convulsions begin with a stiffened phase and progress to rhythmic jerks.^6-8 Myoclonic convulsions manifest as brief repeated contractions and may occur synchronously or erratically in the limbs, trunk, or face.^6-8

Ultimately, it is the seizure’s origin, pattern of spread, and involved brain networks that determine the signs and symptoms of a seizure.³ Focal or partial seizures involve one region of the brain, whereas in generalized seizures there is simultaneous abnormal cortical neuron firing involving bilateral hemisphere networks.⁸

Partial seizures are further classified by degree of impaired consciousness. In a simple partial seizure, awareness is preserved, whereas with a complex partial seizure, the patient experiences some degree of impaired consciousness or mental status change.^4,5 Partial seizures also may present initially with preserved awareness before the abnormal cortical activity spreads to both hemispheres to become a generalized, typically tonic-clonic, seizure, in a process known as secondary generalization.³

Absence seizures are seen more frequently in children and manifest as several seconds of staring and loss of awareness, with or without associated automatisms (e.g., blinking, lip smacking), followed by a quick return to baseline.^3,8 These are classically referred to as petit mal seizures.³

Aura also is used to describe a focal onset seizure, often originating in the temporal lobe, whereby the patient may experience a déjà vu sensation usually before experiencing a transient altered awareness or generalized convulsive seizure.^4,5,8 The aura often will be described as an epigastric “rising” sensation or abnormal taste or smell prior to the onset of seizure activity.⁹

The term postictal refers to the interval period following seizure activity before the patient returns to their baseline mental status.⁸ Todd’s paralysis refers to transient postictal paralysis, which typically resolves within 30 minutes of the seizure.^8,10

Epilepsy, also sometimes referred to as a seizure disorder to minimize associated stigma, is the clinical condition of recurrent, unprovoked seizures.^6,8 Epilepsy classically was defined by the presence of two or more unprovoked seizures more than 24 hours apart. However, the current definition also includes patients with “one unprovoked seizure and the probability of further seizures similar to the general recurrence risk after two unprovoked seizures (approximately 60%), occurring over the next 10 years.”¹¹ As described earlier, epileptic seizures can have a wide clinical presentation ranging from generalized convulsive seizures with tonic-clonic activity to absence seizures.

Status epilepticus has been defined as a seizure lasting more than 30 minutes or intermittent seizures without returning to baseline for more than 30 minutes.^12,13 However, studies have indicated that irreversible neuronal injury occurs before 30 minutes and that pharmacoresistance to antiepileptic drugs worsens as seizure activity continues.^4-6 Consequently, an updated definition of seizure activity lasting greater than five minutes has been proposed but is inconsistently applied in the research literature.¹²

Nonconvulsive status epilepticus presents as a persistent change (greater than 30 minutes) in behavior from the patient’s baseline with absent or clinically subtle motor symptomatology.^6,10 Patients may be noted to have facial or limb twitching, gaze deviation, nystagmus, or a persistent altered mental status without motor findings. They may exhibit what are referred to as negative symptoms, such as aphasia, mutism, amnesia, catatonia, or decreased level of responsiveness.^10,14

Nonconvulsive status epilepticus remains a clinically challenging diagnosis for clinicians, requiring electroencephalogram (EEG) for definitive diagnosis.^4,5,10 Nonconvulsive status epilepticus should be considered in patients with coma of undetermined etiology and in patients who do not return to baseline following a convulsive seizure.^4,5,10

Epidemiology

In 2019, seizure was the primary diagnosis in an estimated more than 760,000 patients (about 0.5% of total visits) who presented to an ED in the United States.¹⁵ However, this does not account for the many patients who present to the ED with the concern for seizure who, in fact, have experienced a seizure mimic. In a review of ED patients evaluated for seizure between 1993 and 2003, patients were more likely to be male (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.3-1.5), African Americans (OR, 1.4; 95% CI, 1.3-1.6), and with an alcohol-related visit (OR, 3.2; 95% CI, 2.7-3.9).¹ A bimodal age distribution is seen in all patients regardless of gender, with a higher incidence in infants (253 per 100,000 ED visits) and in the elderly older than age 75 years (123 per 100,000 ED visits).¹⁴

While approximately 8% to 10% of the population will experience a seizure during their lifetime, only 2% to 3% of patients ultimately will develop epilepsy.¹⁵ Unfortunately, despite initiation of appropriate therapy, up to 50% of patients with epilepsy will have recurrent seizures, and up to 10% will have intractable epilepsy.^4,5

Most seizures evaluated in the ED are secondary to an underlying disease process. This includes febrile seizures, which account for 28% of all pediatric ED seizure evaluations.² In a prospective study from 11 university-affiliated EDs over a two-year period, the three most commonly identified diagnoses in 1,348 patients older than 5 years of age who underwent neuroimaging for suspected seizure were alcohol and drug use (19%), head trauma (8%), and epilepsy (7%).¹⁷ Other less frequent pathology included brain neoplasm (3%), metabolic abnormalities (3%), and stroke (3%).¹⁷ In another study, alcohol withdrawal was attributed to up to 28% of provoked seizures in the ED, making it the largest group of patients with an identified etiology.¹⁸

Status epilepticus is relatively uncommon, with a prevalence of 6 per 1,000, but trend studies have demonstrated an increase in incidence in the last few decades.^4,5,19 A slight majority of status epilepticus cases (54%) present in the absence of known epilepsy and tend to occur as early as the first or second unprovoked seizure.¹⁹ Overall, the mortality for status epilepticus in adults appears stable at about 20%, with worse outcomes associated with prolonged seizure activity.¹⁸

Nonconvulsive status epilepticus with its more subtle or even absent clinical manifestations is more challenging to estimate prevalence. Nonconvulsive seizures are likely grossly underdiagnosed, since several studies have revealed that 20% of critical care patients have nonconvulsive seizures and that most seizures in the intensive care unit are nonconvulsive (92%).¹⁴ Nonconvulsive status epilepticus can be seen in all age groups and even as a primary manifestation of a seizure disorder. Incidence rates vary between 2 and 20 cases per 100,000 individuals.^{4, 5}

Etiology

Seizures can be further classified by etiology, whether they are provoked or unprovoked. A provoked seizure, also known as an acute symptomatic seizure, is one that occurs in close temporal association to a precipitating insult, typically defined as within seven days.^6,14 Common precipitants of provoked seizures include alcohol withdrawal, acute hemorrhagic and ischemic stroke, infection, closed head injury, medication- or substance-induced, metabolic derangements, autoimmune/inflammatory causes, and neoplasm.¹⁴ Unprovoked seizures in a patient with no known history of seizures raises concern for a primary seizure disorder.

Patients with a primary seizure disorder may continue to have seizures despite treatment with antiepileptic drugs (AEDs). These seizures, referred to as breakthrough seizures, occur in about 20% to 30% of patients with epilepsy.²⁰ The most common cause of breakthrough seizures is subtherapeutic levels of antiepileptic medications, which may occur for various reasons.²⁰ Poor adherence is the main reason for subtherapeutic levels, which may be due to side effects discouraging patients from taking their medications, the cost of filling prescriptions or copays for office visits for new prescriptions, and in some patients, poor insight into their diagnosis and the treatment needed.²⁰ Other reasons for subtherapeutic levels include inadequate dosing, the initiation of new medications with competing pharmacokinetics causing enhanced clearance of AEDs, and acute gastrointestinal disease (e.g., gastroenteritis) interfering with medication absorption.²⁰

Breakthrough seizures also may occur in patients who demonstrate drug resistance to certain classes of AEDs or have progression disease.²⁰ Additional factors that lower the seizure threshold and result in breakthrough seizures include alcohol use, sleep deprivation, emotional or physical stress (e.g., exercise, fever, or infection), use of stimulants, metabolic abnormalities, pregnancy, and other conditions that increase estrogen (epileptogenic) or decrease progesterone levels (antiseizure).^20,21

Pathophysiology

A seizure is the clinical manifestation of uncontrolled, abnormal, synchronous electrical discharges in the cerebral cortex. Homeostasis of electrochemical gradients across the neuronal membrane is maintained by a delicate balance of excitatory and inhibitory neurotransmitters. The major excitatory neurotransmitter is glutamate, which acts on several receptor subtypes, most notably N-methyl-D-aspartate (NMDA) receptors, to provoke an action potential.²² Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter, which acts on GABA_A and GABA_B receptors to inhibit action potentials.²²

Numerous factors contribute to the ability to generate an action potential, referred to as neuron excitability, and include the number and type of neurotransmitter receptors, biochemical modification of receptors, and the concentration of extracellular ions.²² When the balance of these factors is disrupted, a state of excessive excitability and decreased inhibition may occur, resulting in synchronous discharges of susceptible neurons, producing a seizure.²² This equilibrium may be disrupted by an acute pathologic process, such as infection, toxin, electrolyte derangements, trauma, or ischemia.²³ With resolution of the acute abnormality, the risk of seizure resolves. However, if cortical networks remain perturbed, epilepsy may develop.

With chronic and persistent seizure activity there are changes in neurotransmitters and their receptors that enhance neuron excitability, making seizures more frequent and more resistant to treatment.¹⁹ Over time, there is decreased GABA_A receptor expression secondary to receptor internalization and degradation, leading to decreased inhibitory regulation by endogenous GABA and, subsequently, sustained epileptiform activity.¹⁹ While most abortive therapies act on GABA_A subtype receptors, resistance to GABAergic drugs, such as benzodiazepines, barbiturates, and propofol, likely is related to this decrease in postsynaptic GABA receptors.¹⁹ In addition, there often is a concomitant increase in NMDA receptors, which further increases neuronal excitability.¹⁹

Clinical Features

Often the patient is no longer seizing upon their arrival to the ED. A comprehensive history and physical exam, therefore, are essential in differentiating a seizure from mimics, identifying precipitating factors, and determining whether a patient with known epilepsy has developed new semiology. A witness account often is paramount, since the patient may have lost consciousness during the event or may be persistently disoriented, confused, or drowsy, as is characteristic in the postictal period. It is important to inquire about the duration, nature of any abnormal motor movements or other physical manifestations such as posturing, eye opening, or eye deviation, and timeline of recovery. The witness also may describe head trauma or other injury requiring additional evaluation and workup.

The physical exam is neither sensitive nor specific for detecting or excluding seizures, but in the appropriate clinical context, it can increase suspicion for seizure activity. The presence of a bite injury to the tongue, usually on the lateral aspect, is suggestive of seizure with a likelihood ratio of 8.2 (95% CI, 2.0-22.5) when compared to syncope.²⁴ Contrary to popular belief, urinary incontinence is not specific to seizure activity and has a likelihood ratio of 0.88 (95% CI, 0.71-1.10).²⁵ Postictal confusion, preceding aura or déjà vu sensation, head or eye turning to one side, rhythmic limb shaking, and dystonic posturing are strongly suggestive but not diagnostic of seizure activity.^4,5 The focused neurologic examination may reveal the presence of transient focal neurologic deficits, known as Todd’s paralysis.

When seizure activity continues beyond five minutes, the patient should be considered to be in status epilepticus, which can be convulsive or nonconvulsive as mentioned previously. Generalized convulsive status epilepticus may be seen even in patients without a history of epilepsy, such as with infection, trauma, or hemorrhage.¹² Any patient who does not recover consciousness after a single convulsive seizure, but instead remains unresponsive following the event, should raise concern for nonconvulsive status epilepticus.¹⁰

Diagnostic Studies

For any patient actively seizing, the initial approach is no different than that of any critical patient. Ensure patient safety by moving the patient away from anything that could result in injury or trauma. The patient’s airway, breathing, and circulation should be assessed. It is important to note that nothing should be inserted into the mouth, including a tongue sweep, since this could result in the patient choking or in an injury to the provider. Vital signs should be obtained as soon as possible with a goal oxygen saturation greater than 92%.²⁶ It is critical to evaluate blood glucose using a point-of-care device, since both hypoglycemia and hyperglycemia can trigger seizure activity.¹⁴

When seizure activity has resolved, a general and focused neurological examination should be performed. Findings such as neck stiffness, photophobia, and Kernig’s and Brudzinki’s signs are suggestive of meningitis.¹⁴ The provider also should evaluate for pupillary dilatation, photophobia, and papilledema, which might suggest elevated intracranial pressure.¹⁴ Forced gaze deviation, myoclonus, altered consciousness, and nystagmus may suggest ongoing seizure activity that requires urgent pharmacologic intervention.¹⁴

If a patient has not returned to their baseline mental status, cardiac monitoring with supplemental oxygen should be initiated. If there is evidence of respiratory compromise or persistent hypoxemia, the patient should undergo rapid sequence intubation. Rocuronium may be preferred over succinylcholine in this scenario given the risk of hyperkalemia and elevated intracranial pressure with the latter paralytic.¹⁴ Vasopressors and intravenous fluid should be administered for hypotension as clinically indicated.

First-Time Seizure

Patients with a first-time seizure, even those who return to their clinical baseline, should be evaluated for an underlying cause. Initial laboratory evaluation should include a complete blood count, basic metabolic panel, calcium level, magnesium level, serum or urine toxicology screen, liver function tests, urinalysis, as well as blood and urine cultures when appropriate.¹⁴ In a patient with fever, a broad evaluation for possible infection should be performed, including consideration of a lumbar puncture to rule out a central nervous system (CNS) infection, such as meningitis or encephalitis.¹⁴ When CNS infection is suspected, prompt initiation of broad-spectrum intravenous (IV) antibiotics, including acyclovir, should not be delayed and may be initiated prior to the lumbar puncture.¹⁴ Other infectious etiologies, such as upper respiratory tract infections and urinary tract infections, may lower the seizure threshold and provoke a seizure.¹⁴ Consequently, a low threshold should be considered for obtaining a chest X-ray and initiating an infectious workup in all first-time seizure patients.

Diagnostic imaging should be obtained in patients presenting with a first-time seizure, although there is no consensus regarding which modality is preferred.^27,28 Head computed tomography (CT) is readily available, quick, and an easy study to obtain in most EDs, and can aid in identifying stroke, neoplasm, and abscess as inciting events for the seizure. Additionally, in patients presenting with head trauma, emergent head CT is indicated to identify subdural hematoma, traumatic subarachnoid hemorrhage, or other intracranial hemorrhage.^14,28

However, brain magnetic resonance imaging (MRI) has superior sensitivity for detecting a seizure cause and ultimately identifies an epileptogenic lesion in 8% of patients with a normal head CT.²⁷ Epileptogenic pathologies most likely to be visible on MRI but not CT include mesial temporal sclerosis, malformations of cortical development, and cavernomas.²⁷ Consequently, if MRI is readily available, there may be scenarios in which an emergent head CT is not indicated. However, if MRI is difficult to arrange or the ability to follow up urgently is in question, then head CT should be obtained in the ED as part of the initial evaluation.²⁷

Known Seizure Disorder

Patients with a known seizure disorder who present with seizure may be experiencing a breakthrough seizure because of medication non-compliance or an acute stressor that lowers the seizure threshold. Information from family and witnesses should focus on whether the seizure was typical or atypical for the patient. In the setting of a typical seizure that resolves within three to five minutes without intervention and where the patient rapidly returns to baseline, further evaluation with laboratory testing and imaging may not be necessary.²¹

Delayed or missed medication doses suggesting AED non-compliance is the most common cause of recurrent seizure among ED patients.^4,5,20 However, careful history should be obtained to assess for other possible seizure triggers, such as recent changes to AEDs, new medications or supplements, recent illness, sleep deprivation, and physiologic or psychological stressors.^20,21 Gastroenteritis may affect absorption and result in subtherapeutic levels of AEDs.²⁰ Additionally, recreational drugs (e.g., cocaine, phencyclidine [PCP], and ecstasy) are known to decrease the seizure threshold in those with underlying seizure disorder.^4,5

Basic laboratory studies in patients with a known seizure who present with a typical (for them) seizure and quickly recover back to baseline often are not necessary unless additional history has been provided that raises concern for a specific pathology.^20,21 However, serum levels of specific AEDs may be helpful in titrating the patient’s dose in conjunction with the patient’s neurologist.^20,21 Unfortunately, hospital laboratories usually have the ability only to measure phenytoin, valproate, carbamazepine, and phenobarbital levels on a STAT basis. New or atypical seizure activity may indicate a new epileptiform lesion or progression of disease, and these patients warrant further evaluation with an emergent head CT.^20,21

Emergent brain imaging also should be considered for patients on antiplatelet or anticoagulant therapy, with known intracranial lesions, immunocompromise, trauma, fever, or prolonged postictal time.^20,21,28 As with first-time seizure evaluation, a lumbar puncture should be considered in patients with severe headache, fever, persistent altered mental status, or underlying immunocompromise, to assess for subarachnoid hemorrhage and meningitis/encephalitis.^20,21 Any patient who has not returned to their clinical baseline or has lingering neurologic signs or symptoms will require comprehensive evaluation with laboratory studies and imaging.^20,21,28

Differential Diagnosis

The differential diagnosis is paramount since many other acute illnesses can mimic seizures and vice versa. (See Table 2.) The most common seizure mimic is syncope, and syncope can be caused by or associated with a variety of disorders.²

The diagnosis of seizure often is clinically suspected based on history and exam. EEG can provide definitive diagnosis but often is not readily available in the ED setting.¹⁰ Additionally, there is a decreased likelihood of capturing epileptiform activity with increasing time since the event.¹⁰ It is estimated that up to 20% of patients with epilepsy are misdiagnosed, resulting in unnecessary treatment with AEDs.¹⁰ The most common misdiagnoses are syncope and psychogenic nonepileptic seizures (PNES).¹⁰

Syncope

Syncope is a sudden loss of consciousness due to inadequate cerebral perfusion. Up to 40% of patients with syncope will experience some motor component, such as myoclonic jerks after loss of consciousness, which commonly are mistaken for seizure activity.^4,5 This phenomenon is termed convulsive syncope and usually is not associated with tongue biting or cyanosis.^4,5 Additionally, syncope often may be distinguished from seizure by a rapid return to normal consciousness.^6,10

Syncope can be categorized as cardiac, orthostatic, or neurocardiogenic in origin.¹⁰ Cardiac syncope is due to structural heart disease or cardiac dysrhythmia. A history suggesting possible cardiac syncope includes older age, chest pain, syncope during exertion, absence of prodrome, or preceding palpitations.¹⁰ Orthostatic syncope occurs with hypovolemia and may be seen secondary to dehydration, bleeding, autonomic dysfunction, or as a medication side effect.^9,10 Orthostatic blood pressure measurement may assist in the diagnosis of orthostatic syncope. Neurocardiogenic or vasovagal syncope occurs due to reflexive increased vagal tone, such as with coughing, defecation, micturition, or carotid sinus hypersensitivity, and is more commonly seen in younger patients.^9,10

Psychogenic Nonepileptic Seizures

PNES consist of movements resembling epileptic seizures but do not result from abnormal cortical electrical activity.^10,29 These seizures, also known as psychogenic seizures and pseudoseizures, may present in patients with or without an underlying neurogenic seizure disorder.^4,5 Clinical presentation with asynchronous movement of extremities, closed eyes, resistance to eyelid opening, geotropic eye movements (eye deviation downward in the direction that the head is turned), mouth closure during the tonic phase, rapid head movements, and pelvic thrusting all are highly suggestive of PNES.^4,5,10,29 Up to 70% of patients with PNES have a psychiatric illness, most commonly depression, post-traumatic stress disorder (PTSD), and personality disorders.¹⁰ The gold standard for diagnosis is video EEG, which demonstrates no epileptiform abnormalities before, during, or after an event.^10,29

Other Neurologic Disorders

Other common seizure mimics are primarily neurologic disorders, including stroke or transient ischemic attack (TIA), sleep disorders, movement disorders, and migraines. Cerebral ischemia may cause symptoms that overlap with seizures, such as gaze deviation and altered mental status.¹⁰ A full neurologic exam as well as neurologic and neurovascular imaging are essential to rule out ischemia when the diagnosis is unclear.

Narcolepsy with cataplexy also may present similar to seizures.¹⁰ Narcolepsy is a sleep disorder occurring in 1/2,000 people and is characterized by excessive daytime sleepiness with lapses into sleep at least three times per week for at least three months.¹⁰ The sudden loss of tone seen in cataplexy, often in response to emotion, is not always present with narcolepsy.¹⁰ Narcolepsy is a clinical diagnosis supported by polysomnography and multiple sleep latency testing.¹⁰

Movement disorders that may be confused for seizure include dystonia, Parkinson’s disease and secondary parkinsonism, Huntington’s disease, Tourette syndrome, and tardive dyskinesia, among others. Movement disorders often can be distinguished from seizures on clinical evaluation and frequently are supported by contributing patient history.^30-32 Furthermore, movement disorders typically do not alter mental status or consciousness.¹⁰

Finally, migraines may present with concurrent neurologic symptoms, such as numbness, weakness, or loss of consciousness, which may overlap with potential seizure symptomatology.¹⁰ Specifically, migraine auras may be like focal seizures with visual symptoms or seizure aura.¹⁰ The classic history of unilateral headache exacerbated by physical activity with associated photophobia, phonophobia, nausea, and vomiting all are suggestive of migraine diagnosis.¹⁰

Initial Treatment of Active Seizures

In patients presenting with an active seizure, medications should be administered as quickly as possible because the longer the seizure continues, the more difficult it may be to achieve pharmacologic control.²⁶ Guidelines on management from the American Epilepsy Society and Neurocritical Care Society recommend an IV benzodiazepine be administered within the first five minutes of seizure activity. (See Table 3.) Lorazepam generally is the preferred agent because of its smaller volume of distribution, which results in an anticonvulsant effect of up to 12 hours, while conversely, the anticonvulsant effect of diazepam can last as little as 20 minutes.^4,5 If after five minutes the seizure persists, a repeat dose of IV lorazepam should be administered.²⁶

Intramuscular (IM) midazolam is a safe and effective alternative for seizure cessation and often is used in the prehospital setting when intravenous access is not available.³³ Additionally, the RAMPART study, a double-blind, randomized controlled trial, demonstrated noninferiority of IM midazolam and IV lorazepam.³³ Finally, IV diazepam may be considered, if necessary, but it has been shown to be less effective than both lorazepam and midazolam.³⁴

If benzodiazepines are not successful on repeat administration, a second-line, non-benzodiazepine agent should be considered.^35-37 Repeated doses of benzodiazepines lead to delayed termination of status epilepticus.³⁵ The airway should be assessed and secured via endotracheal intubation if a second-line agent is to be given.

Phenytoin and its prodrug fosphenytoin are common second-line therapies, but fosphenytoin typically is preferred because it can be administered at a faster rate and has less risk of QT prolongation, cardiac arrhythmias, and hypotension.³⁶ Additionally, fosphenytoin has a lower risk of complications with extravasation compared to phenytoin, which can cause severe tissue necrosis.¹⁹ In spite of this improved safety profile, the fosphenytoin manufacturer still recommends cardiac and blood pressure monitoring with fosphenytoin infusion because hypotension still may occur.^4,5

Valproic acid is an acceptable alternative second-line agent that is suggested to be equally effective as fosphenytoin with minimal adverse side effects.³⁶ It is recommended for both emergent treatment of seizures as well as refractory status epilepticus based on high-level evidence.¹² It may be infused rapidly without hypotension and cardiac arrhythmias.³⁶ It is generally very well tolerated except for rare cases of idiopathic hepatotoxicity and should be avoided in patients with underlying hepatic dysfunction.^4,5 Other second-line agents include phenobarbital, midazolam, levetiracetam, and lacosamide; however, the supporting data for their use are less robust.³⁶

When seizures continue despite treatment with a benzodiazepine and a second-line anticonvulsant therapy, the patient is termed as being in refractory status epilepticus and a third-line treatment should be initiated within one hour.^36,37 An alternative second-line agent may be tried, but providers should strongly consider escalating to continuous infusion of an anesthetic agent to prevent further seizure propagation.^35,36,38 These agents include midazolam, propofol, or barbiturates, such as phenobarbital, pentobarbital, or thiopental.^36-38 Barbiturates are associated with lower rates of treatment failure and seizure recurrence but unfortunately have a higher risk of cardiac depression, hypotension, paralytic ileus, and infection.³⁶ All these third-line agents cause respiratory depression, and infusion necessitates definitive airway management and pressors if needed for concomitant cardiopulmonary depression.^4,5

Midazolam, which is water-soluble with high CNS penetration, has a short duration of action and is easily titratable. It is also notable for causing less hypotension than propofol and barbiturates.^4,5 However, midazolam should be avoided in patients with renal failure because it is renally excreted and may be associated with tachyphylaxis with prolonged use.³⁶

Propofol functions as a CNS depressant by acting directly as a GABA agonist and NMDA antagonist, and it is typically dosed as a bolus followed by a continuous infusion. Ultimately, however, there is no clear evidence of superiority between agents, and the selection often is made by physician preference.

Management After Seizure Cessation

Initiation of an antiepileptic drug in the ED for long-term management of seizures may be considered to prevent seizure recurrence. After a first-time unprovoked seizure, patients have an approximately 35% risk of seizure recurrence in the next five years, even in the presence of a normal neurologic exam, normal MRI brain, and normal EEG.³ The risk is even higher in patients with known neurologic disorders, developmental delay, history of febrile seizures, or family history of epilepsy.³ It is recommended that adults with a first-time unprovoked seizure be informed of this risk.³⁹

Immediate initiation of AEDs is likely to reduce the risk of seizure recurrence within the first two years, but may not improve quality of life, and over a longer term (more than three years) is unlikely to contribute to sustained seizure remission.³⁹ The rate of adverse events from AEDs ranges from 7% to 31%, although side effects typically are mild and reversible.³⁹ (See Table 4.) Thus, the decision of whether to initiate AEDs in patients with an unprovoked seizure should come from shared decision making.³⁹

In patients with a first-time provoked seizure, treatment should be aimed at treating the underlying cause. The American College of Emergency Physicians (ACEP) clinical policy committee offers a Level C recommendation for initiation of AEDs in first-time provoked seizures and in first-time unprovoked seizures if the latter has no evidence of brain injury or disease.¹² Conversely, if the patient has a remote history of stroke or traumatic brain injury, the patient is at an increased risk of recurrent seizures, and initiation of antiseizure medications may be considered with or without a consulting specialist (Level C).^3,12

If the diagnosis of epilepsy is established, then AEDs are the first-line treatment. The choice of AED is largely individualized, with consideration of tolerance of side effects, other concomitant medications, and underlying medical and psychiatric conditions. Therapies are divided into narrow and broad-spectrum agents, with the latter demonstrating efficacy in both focal and generalized seizure epilepsies. Narrow-spectrum agents typically are effective in focal seizures regardless of secondary generalization or alteration in consciousness.¹⁶

Additional Aspects

Alcohol Withdrawal Seizures

Chronic alcohol use affects the balance of GABA and glutamine, the primary inhibitory and excitatory neurotransmitters in the CNS, respectively.⁴⁰ When alcohol is abruptly discontinued or removed, a hyperexcitable state occurs, leading to the development of alcohol withdrawal syndrome and, potentially, seizures.⁴⁰ Alcohol withdrawal seizures usually occur within six to 48 hours after cessation of alcohol consumption. These seizures typically are generalized tonic-clonic and may be a major precipitant of status epilepticus, representing 9% to 25% of all status epilepticus cases.⁴¹

The severity of alcohol withdrawal symptoms increases with repeated episodes, a process referred to as kindling.⁴¹ As such, early manifestations of alcohol withdrawal, such as tremors, agitation, and autonomic instability, should be treated aggressively.⁴² The mainstay of withdrawal treatment is symptom-triggered therapy with benzodiazepines, which has been shown to prevent progression to withdrawal seizures.^43,44

Benzodiazepines remain the first-line treatment for individuals presenting with alcohol withdrawal seizures.^4,5,44 Diazepam may be preferred over lorazepam given its shorter onset of action and longer serum half-life due to active metabolites, but specific consideration should be made for local institutional protocols.⁴⁵ Phenobarbital often is considered an adjunctive therapy given its synergistic effects with benzodiazepines, but it should be reserved for patients refractory to benzodiazepine therapy.⁴⁵

In patients with severe withdrawal refractory to benzodiazepines and/or barbiturates, propofol has been shown to be effective in mechanically ventilated patients.⁴⁵ Propofol functions as a GABA receptor agonist as well as an antagonist at NMDA receptors, thus targeting both pathways chronically modulated in chronic alcohol use.⁴⁵

It is important also to consider other potential etiologies in seizures assumed to be alcohol related. One study found an alternate diagnosis in 54% of an initial cohort thought to be alcohol-withdrawal seizures.⁴¹ Recognition and treatment of other life-threatening causes of seizures should be considered, such as CNS infection, hypoglycemia, and intracranial hematoma.⁴²

Pregnancy

Seizures during pregnancy may be the result of an underlying seizure disorder or eclampsia and represent a unique clinical challenge with high risk to the mother and infant. Seizure control in the patient with underlying epilepsy typically is the same as in the nonpregnant patient, with benzodiazepines used first-line for abortive therapy.³⁶

Eclampsia, which most commonly presents as a generalized tonic-clonic seizure, is the severe manifestation of preeclampsia, characterized by hypertension with evidence of end-organ involvement (e.g., thrombocytopenia, elevated transaminases, renal insufficiency, pulmonary edema, or new-onset neurologic symptoms) after the 20th week of gestation.^46,47 Eclampsia is associated with perinatal mortality and may present before, during, or after labor.⁴⁷ The frequency of postpartum eclampsia ranges from 11% to 44%, with the majority occurring in the first 48 hours following delivery.⁴⁸

Treatment of eclampsia involves IV administration of magnesium sulfate 4 g to 6 g loading dose over 15 to 20 minutes, followed by a maintenance dose of 1 g/hour to 2 g/hour.^47,48

Eclamptic seizures may be preceded by a severe and persistent headache, photophobia, blurred vision, right upper quadrant or epigastric pain; however, it also may present without any prodromal symptoms.^47,49 Even hypertension and proteinuria, the hallmark of preeclampsia, may be absent in up to 38% of cases before the seizure episode.⁴⁷ Therefore, eclampsia should be considered in all patients who are at least 20 weeks pregnant and up to six weeks postpartum presenting with seizure. Ultimately, definitive treatment of eclampsia is delivery of the fetus.⁴⁷

If the seizure is resistant to magnesium (still seizing after 20 minutes or more than two recurrences), alternative diagnoses should be considered, since most cases had abnormal findings on brain imaging.⁴⁷ About 10% of women will have a second seizure after the initial magnesium bolus.⁴⁸ These patients should receive an additional bolus of 2 g magnesium sulfate IV over three to five minutes.⁴⁸ If a patient has a third seizure or has continued to seize through treatment with magnesium, IV benzodiazepines are needed with escalation of treatment like that for nonpregnant patients with status epilepticus.⁵⁰

Seizure Prophylaxis

Intracranial pathology is a significant risk factor for the development of seizures, and patients with intracranial hemorrhage may present with an acute symptomatic or provoked seizure. The incidence of post-traumatic seizure after a subdural hematoma is 15% to 36%.^14,21 Subarachnoid hemorrhage also may precipitate seizures, with a risk of 6% to 26%.²¹ Intraparenchymal hemorrhage carries a 14% risk of provoked seizure, most notably in lobar intracerebral hemorrhage.¹⁴ Patients with intracranial bleeding who present with seizures should be treated with an AED, and treatment should continue until the insult has resolved.²¹ In patients not presenting with seizure activity, AED prophylaxis frequently is initiated and recommended by our neurology and neurosurgery colleagues; however, the evidence supporting this practice is limited and remains controversial.^21,51

Seizures also may occur in the setting of ischemic stroke as an early symptomatic presentation or remote (late) post-stroke complication. The acute period is more broadly defined as ranging between seven to 30 days after the stroke.²¹ Seizure develops in about 8.9% of patients with ischemic stroke, with higher risk in larger infarct size and cortical stroke.¹⁴ Because of the relatively low incidence of later development of unprovoked seizures, initiation of long-term AED treatment is not usually recommended at the time of the acute presentation.²¹ However, some patients with remote symptomatic seizures ultimately may experience recurrent unprovoked seizures, with up to 90% eventually diagnosed with poststroke epilepsy.²¹ Seizure prophylaxis in patients diagnosed with brain tumors in the ED is similarly not recommended in the absence of presenting seizure activity.²¹

Toxin-Induced Seizures

Seizure activity resulting from toxins is not uncommon, with up to 6% of new-onset seizures and 9% of status epilepticus cases attributed to drugs or poisons.⁵² (See Table 5.) Seizures may occur if toxins cause an imbalance in the CNS excitation-
inhibition equilibrium. Toxins can interrupt normal neuronal pathways via action on specific excitatory or inhibitory transmitters and receptors, disturbances in ion flux that affect membrane depolarization, and changes in concentration or activity of biogenic amines (e.g., serotonin, dopamine, norepinephrine, epinephrine, and histamine) and acetylcholine.^52-54

Drugs and toxins also can provoke seizure activity as the result of an indirect effect on brain perfusion, oxygenation, or metabolic disturbances.^52-54 Some toxins directly affect the heart and may induce cardiac arrhythmias.⁵² Others, such as carbon monoxide and cyanide, are mitochondrial toxins, inducing cellular hypoxia.⁵²

Most toxin-induced seizures will manifest as generalized tonic-clonic activity, and the management is supportive care with airway and cardiopulmonary stabilization followed by prompt administration of a benzodiazepine.⁵⁴ Toxin-induced seizure activity typically is self-limited, so if seizure activity does not terminate despite two doses of a benzodiazepine, administration of pyridoxine should be considered.^53,55 Pyridoxine is an essential cofactor in the formation of GABA. Therefore, a deficiency in GABA develops when pyridoxine is inactivated or depleted, predisposing the patient to seizure activity. Activation of pyridoxine is inhibited by isoniazid, a common treatment for tuberculosis. Pyridoxine may be depleted in pregnancy, reduced with use of levodopa/carbidopa, and may be deficient from decreased dietary intake.^52,55 Empiric dosing of pyridoxine is 5 g IV in adults and 70 mg/kg in pediatrics.⁵²

Importantly, phenytoin is not recommended as a general treatment of toxin-mediated seizures since it has been shown to be ineffective in terminating seizures in a variety of drug-induced and withdrawal seizures.^52,53 Furthermore, phenytoin may potentially be harmful in seizures caused by lidocaine, theophylline, or tricyclic antidepressants based on animal studies.^52,53

It is important to note strychnine and tetanus both induce convulsive activity that resembles seizure activity but does not originate in the cerebral cortex.^52,53 These involuntary contractions, myoclonus, hyperreflexia, and opisthotonos result from the absence of normal glycine inhibition in the spinal cord and brainstem as the result of the toxin’s activity.⁵² The so-called “spinal seizures” are characterized by a normal mental status until the patient becomes hypoxic due to impaired ventilation.⁵²

Disposition and Prognosis

The 30-day mortality risk following an acute symptomatic seizure is about 20%, with higher mortality rates seen in subgroups older than 65 years of age and with seizures due to stroke, traumatic brain injury, and CNS infection.¹⁴ The best predictor of seizure recurrence is underlying etiology and EEG findings, neither of which are readily available to most emergency physicians.^4,5

In the case of the critically ill patient or status epilepticus, the need for hospitalization is clear because these patients will require extended workup and treatment. However, the disposition of the patient who has returned to baseline or has a first-time seizure is more controversial. In general, while MRI and EEG may be necessary for guiding AED selection, ACEP does not recommend admission for patients with a first-time unprovoked seizure who have returned to their baseline.¹²

A disposition algorithm was proposed by Dunn and colleagues that suggests these patients can be discharged safely provided they have returned to their clinical baseline with no neurologic signs or symptoms, have normal vital signs, have a responsible adult to watch them, have follow-up arranged, and are likely to follow up.⁵⁶

Summary

Seizures are a common neurologic emergency to present to the ED. Acute symptomatic seizures require careful consideration of comorbid diseases and potential provoking etiologies. While epilepsy is a condition of recurrent seizures, most seizure patients evaluated in the ED do not have epilepsy, even when presenting with status epilepticus.^4,5

Acute management of the actively seizing patient necessitates rapid stabilization and prompt administration of benzodiazepines. If seizure activity continues, aggressive escalation with second-line therapies, such as phenytoin, fosphenytoin, or valproic acid, should be initiated as soon as possible. In the patient with refractory status epilepticus, the patient should be considered for anesthetic treatment and transition to mechanical ventilation.

The patient presenting with a first-time seizure should be evaluated with focused laboratory testing and diagnostic imaging. In the patient with a known seizure disorder who rapidly returns to baseline, further evaluation with laboratory tests and imaging may be not necessary. However, when a patient presents for seizures, regardless of seizure history, with concurrent fever, immunocompromise, comorbid disease, or focal neurologic deficits, admission is recommended for continued evaluation and testing.

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