The emergent evaluation and treatment of generalized convulsive status epilepticus presents challenges for emergency physicians. This disease is one of the few in which minutes can mean the difference between life and significant morbidity and mortality. It is imperative to use parallel processing and have multiple treatment options planned in advance, in case the current treatment is not successful. There is also benefit to exploring, or initiating, treatment algorithms to standardize the care for these critically ill patients.
Key points
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Status epilepticus (SE) is diagnosed at 5 minutes of continuous seizure activity, and has the potential for high morbidity and mortality if not diagnosed promptly and treated accurately and effectively.
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Devising specific protocols for management of SE improves outcomes.
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The first line for management of SE is benzodiazepines, followed by phenytoin, fosphenytoin, or valproic acid.
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Second line adjuncts for management of SE are levetiracetam, lacosamide, phenobarbital and ketamine, followed by intravenous anesthetics.
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Subtle SE occurs frequently after convulsive SE and should be treated in the same manner.
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Underlying causes leading to provoked seizures should be considered early on in the disease, especially in patients not responding to first line agents.
Introduction
Seizures are commonly encountered in the emergency department (ED) because approximately 5% to 10% of people who live to the age of 80 years experience a seizure. The spectrum of disease, from a partial complex seizure to refractory status epilepticus (SE), can present a daunting treatment task to emergency physicians. Epilepsy is defined as 2 or more unprovoked seizures occurring at least 24 hours apart, a heightened tendency toward unprovoked seizures (as shown by electroencephalographic or neuroimaging testing), or an epilepsy syndrome. The determination of a provoked versus an unprovoked seizure is paramount because the underlying treatment options can be very different. At the far end of the spectrum of disease, generalized convulsive SE (GCSE) can be defined in a variety of ways, but the most common is an active seizure lasting greater than 5 minutes or 2 seizures without return to baseline. There are also subclassifications of subclinical or nonconvulsive, refractory, and super-refractory SE as well. SE is associated with increased morbidity and mortality, with the reported mortality after the first episode of GCSE approaching 20%. The mortality is partly a function of the underlying cause, refractoriness of the seizure, age, and medical comorbidities, with the last 2 factors playing the greatest role. Reported mortality is from 4% to 40%, depending on the definition of SE used in the study and the underlying cause, with hypoxic ischemic brain injury producing the worst outcomes.
The patient’s hospital course from the prehospital setting, continuing through the ED, and ultimately the time spent in an intensive care unit (ICU) can be greatly affected by the choices the emergency physician makes. This article reviews the current diagnosis and treatment recommendations for GCSE, including refractory and other forms of SE.
Introduction
Seizures are commonly encountered in the emergency department (ED) because approximately 5% to 10% of people who live to the age of 80 years experience a seizure. The spectrum of disease, from a partial complex seizure to refractory status epilepticus (SE), can present a daunting treatment task to emergency physicians. Epilepsy is defined as 2 or more unprovoked seizures occurring at least 24 hours apart, a heightened tendency toward unprovoked seizures (as shown by electroencephalographic or neuroimaging testing), or an epilepsy syndrome. The determination of a provoked versus an unprovoked seizure is paramount because the underlying treatment options can be very different. At the far end of the spectrum of disease, generalized convulsive SE (GCSE) can be defined in a variety of ways, but the most common is an active seizure lasting greater than 5 minutes or 2 seizures without return to baseline. There are also subclassifications of subclinical or nonconvulsive, refractory, and super-refractory SE as well. SE is associated with increased morbidity and mortality, with the reported mortality after the first episode of GCSE approaching 20%. The mortality is partly a function of the underlying cause, refractoriness of the seizure, age, and medical comorbidities, with the last 2 factors playing the greatest role. Reported mortality is from 4% to 40%, depending on the definition of SE used in the study and the underlying cause, with hypoxic ischemic brain injury producing the worst outcomes.
The patient’s hospital course from the prehospital setting, continuing through the ED, and ultimately the time spent in an intensive care unit (ICU) can be greatly affected by the choices the emergency physician makes. This article reviews the current diagnosis and treatment recommendations for GCSE, including refractory and other forms of SE.
Pathophysiology
The common pathway for all seizures is an abnormal electrical discharge of cortical neurons, in which a hyperexcitable neuron group fires in a coordinated manner, recruiting adjacent neurons in a synchronized manner. The most common excitatory neurotransmitter is glutamate, which works via the N -methyl- d -aspartate (NMDA) receptor. In contrast, the most common inhibitory neurotransmitter is gamma-aminobutyric acid (GABA), which works via the GABA A receptors. In normal circumstances, the neuronal membrane only allows a single action potential to pass from one neuron to another in a given time interval. Seizures can occur once this stability is altered, which could either be caused by sensitized inhibitory GABA A receptors (eg, in the setting of alcohol or benzodiazepine withdrawal), an altered ion concentration (eg, hyponatremia), or altered cellular metabolism (eg, hypoglycemia). If these mechanisms are involved, these seizures are considered provoked ( Box 1 ).
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Tumor/structural brain lesion
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Vascular:
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Ischemic stroke
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Subarachnoid hemorrhage
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Subdural/epidural hematoma
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Vasculitis
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Toxic:
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Cocaine
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Tricyclics
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Anticholinergics
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Lithium
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Isoniazid (INH)
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Alcohol intoxication/withdrawal
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Benzodiazepine withdrawal
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Pregnancy (eclampsia)
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Metabolic:
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Hyponatremia
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Hypernatremia
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Hypoglycemia
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Hyperglycemia
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Hypocalcemia
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Hypomagnesemia
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Infectious:
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Meningitis/encephalitis
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Brain abscess
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Hypertensive encephalopathy
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Heat stroke
Unprovoked seizures, which by definition are epileptic, are mostly caused by abnormalities of sodium channels, but other mechanisms can be involved, such as self-excitation, abnormal calcium channel stimulation, or a mutation in acetylcholine receptors.
The imbalance of excess excitation and decreased inhibition is what ultimately manifests as a seizure. Many abortive medications, such as benzodiazepines, barbiturates, propofol, and some anesthetics, work via enhancing GABA inhibition. There are many endogenous seizure-terminating processes, which is why most seizures last for only 1 or 2 minutes before spontaneously aborting, but, when they fail, a single seizure is transformed into SE. A seizure that has lasted 30 minutes or more will not spontaneously stop, because at this point the seizure has become self-sustaining even if the inciting factor was removed.
Physiologic Changes in Generalized Convulsive Status Epilepticus
Multiple systemic physiologic changes accompany GCSE, mostly caused by the catecholamine surge. These changes can include hyperthermia, leukocytosis, cerebrospinal fluid (CSF) pleocytosis, increased blood pressure, pupillary dilatation, and other cardiovascular and respiratory abnormalities. Attributing hyperthermia, leukocytosis, and CSF pleocytosis to the seizure is a diagnosis of exclusion, because a true infectious cause needs to be excluded first. As the seizure progresses there can also be resultant lactic acidosis caused by the conversion to anaerobic metabolism as the seizure progresses. The lactic acidosis should clear spontaneously once the clonic nature of the seizures is terminated and normal metabolism returns.
Early during the course of a seizure, brain metabolism is increased, but cerebral blood flow and substrate supply are adequate for demands. Eventually, at some point between 30 and 60 minutes, excitotoxic cell injury occurs, leading to irreversible neuronal damage. In this second phase of SE, brain metabolism remains high, but cerebral blood flow and substrate supply decline, and cerebral autoregulation mechanisms fail, leading to mismatch and decompensation. This detrimental effect on neurons is compounded by systemic hypoxia, hypercarbia, hypotension, and hypothermia, which occur frequently during this second phase. Bradycardia and other arrhythmias can occur as well.
Excitotoxic cell injury is thought to occur when glutamate binds to the NMDA receptors. In normal circumstances, the channel is blocked by a magnesium ion. However, in GCSE the cells are severely depolarized and the magnesium ions are not available, leaving the channel open. This situation allows calcium and other ions to flow into the cell, causing intracellular accumulation of calcium, with resulting acute necrosis, delayed cell death, or both. The length of the early phase depends on an intact airway, oxygenation and circulation, and the ability of the brain to compensate for this increased metabolism, which is decreased in patients with underlying illness.
Pharmacoresistance in Prolonged Seizures
Multiple mechanisms contribute to time-dependent pharmacoresistance in patients with GCSE. Benzodiazepines become less effective because of downregulation and alteration of GABA A receptors, decreasing their availability and affinity for binding. After 20 to 30 minutes of SE, inflammatory changes of molecular transporters decrease transport across the blood-brain barrier, decreasing the affinity of phenytoin and phenobarbital. This process explains why these medications are less effective in controlling a seizure when given later than when given early in the disease process. In addition, the upregulation of NMDA receptors leads to increased excitotoxicity, which is why pharmacoresistance is not thought to occur as much with NMDA antagonists, such as ketamine, making it a potentially attractive option for the treatment of super-refractory SE.
Evaluation and Management
As with all critically ill patients, the focus of evaluation should be on the primary survey, including evaluation of airway, breathing, and circulation. When dealing with neurologic emergencies, and seizures in particular, is important to always obtain a bedside glucose level at the outset of the resuscitation. If possible, the seizing patient should be placed in the lateral decubitus position and protected from harm with padded guardrails.
Airway management
In generalized seizures, the gag reflex is suppressed and vomiting may occur, leading to aspiration of gastric contents. If an airway adjunct is needed, then a nasopharyngeal airway should be used, because oropharyngeal airways and bite blocks are not recommended because of the risk of injury to the provider. The decision to control the airway in a seizing patient is difficult and often anxiety provoking for the emergency provider. If the patient is aspirating or apneic, then immediate intubation is necessary. A patient may need to be intubated after multiple antiepileptic medications are administered. Otherwise, not all patients in SE have to be emergently intubated, because intubation may complicate matters. If the decision is made to intubate the patient on arrival, rapid sequence intubation is recommended, and the recommended agents for this are discussed later in the article.
After assessment of the airway, breathing, and circulatory support, the next step should be to focus efforts on termination of the seizures because this is the most important step in returning the patient to normal physiology. For the reasons listed earlier it becomes exponentially more difficult to manage patients with GCSE as time elapses, so many of the interventions must happen using parallel processing, including obtaining a history and diagnostic testing while concurrently managing the patient. An important consideration is that paralytics eliminate the outwards signs of seizure activity but not the electrical discharges underlying it; therefore, patients intubated for GCSE who are receiving long-acting paralytics should have electroencephalogram (EEG) monitoring.
History
As discussed earlier, seizures can be provoked or unprovoked and obtaining history from emergency medical services (EMS), family members, bystanders, and medical records can be crucial in this determination. Some of the relevant aspects of the history are shown in Box 2 . The relevant history should help determine whether the seizure is provoked and whether there is a reversible or treatable cause to terminate the seizure (see Box 1 ).
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Description of episodes:
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Duration
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Loss of consciousness
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Urinary or stool incontinence
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Tongue biting
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Apnea
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Preceding aura
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Medications (and compliance/possibility of overdose)
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Anticonvulsants
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Tramadol
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Tricyclics
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Lithium
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Isoniazid (INH)
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Past medical history:
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Seizure disorder
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Diabetes mellitus
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Chronic kidney disease
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Cancer
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Alcohol consumption and recent changes in pattern
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Illicit drug use, specifically synthetic cannabinoids, cocaine
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Recent illness, fever
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Trauma
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Pregnancy
Diagnostic testing
Diagnostic tests should be focused on investigating and verifying the relevant history to identify the cause of the seizure and looking for complications from prolonged seizing. Immediate point-of-care glucose level should be measured, if it has not already been by EMS. Serum electrolyte levels (specifically sodium), renal function, and liver function tests should be obtained. A pregnancy test in all women of child-bearing age is necessary. In addition, blood levels of any anticonvulsant medication the patient is on should be done. Even if the results will not be available in a timely fashion, they may help the inpatient team make later decisions. Depending on the history, a toxicology screen for ethanol, aspirin, tricyclic antidepressants, lithium, and drugs of abuse can be obtained, but rarely influences the acute management of SE. If clinically indicated, creatine kinase testing can be ordered to screen for rhabdomyolysis. A lumbar puncture (LP) for suspected meningitis/encephalitis should be done after the patient is stable and the seizure is terminated, but if a strong clinical suspicion exists then empiric antibiotics should be given within 1 hour of arrival and not delayed to perform the LP. Unless there is a clear reason for the seizure (eg, hypoglycemia), noncontrast head computed tomography should be done in all patients with refractory SE once they have been stabilized. There is no role for MRI in acute diagnosis and management of SE. EEG monitoring is not necessary in the initial diagnosis and management of SE, but is recommended (if available) in patients who remain unresponsive after the apparent termination of convulsive SE, those who are pharmacologically paralyzed, and when a patient has been placed in a pharmacologically induced coma in refractory SE. This testing is important to diagnose and appropriately manage subtle SE.
Management
As discussed earlier, there are a few important concepts that govern the successful management of SE. The first is that decreased time to administering abortive medications increases their success rate. Another is that in order to successfully terminate provoked seizures, treatment of the underlying cause must occur. In addition, health care providers need to be vigilant about preventing and treating potential complications of seizures.
The only widely accepted first-line treatment of GCSE is benzodiazepines. There are no nationally accepted treatment protocols for refractory SE, mostly because of a paucity of large randomized controlled studies in humans that show the superiority of one agent to another. Therefore the guidelines, specifically for medications that are second, third, or fourth line, are based on consensus rather than evidence. However, guidelines and protocols are important to provide prompt treatment and improve outcome, and the use of a treatment protocol within an institution results in better and faster seizure control, and decreased hospital and ICU length of stay. The protocol depends on availability of certain medications and familiarity with administration, because rapidity of administration is essential to successfully terminating SE. Fig. 1 shows a tiered approach to the management of SE.
Treatment of underlying conditions
Some seizures are provoked by an underlying cause (see Box 1 ), and the treatment of the causative disorder needs to occur in order to terminate the seizure and improve outcome. The history and/or physical may enable the provider to suspect such conditions, but the refractoriness of the seizure should itself prompt the provider to reconsider such causes. Some of the underlying conditions and specific treatments are listed in Table 1 .
| Cause | Treatment | Notes |
|---|---|---|
| Eclampsia | Magnesium sulfate 4–6 g IV over 15–20 min followed by an infusion of 1–3 g/h Blood pressure control with labetalol (20 mg IV every 10 min) or hydralazine 5–10 mg IV every 20 min | Must monitor magnesium levels |
| Isoniazid | Pyridoxine (B 6 ) 5 g IV at the rate of 0.5–1 mg/min | May repeat every 5–10 min as needed |
| Hypoglycemia | Dextrose 50% 50 mL IV or glucagon 1 mg IM (if no IV access) | — |
| Hyponatremia | 3% hypertonic saline 100 mL IV over 10 min | May be repeated |
| Hypocalcemia | Calcium gluconate or calcium chloride 1–2 g over 10 min | Calcium gluconate is preferred |
| Meningitis | Ceftriaxone 2 g IV q 12 h Plus Vancomycin 15–20 mg/kg IV q 8–12 h | Add ampicillin 1.5–3 g IV q 4–6 h in elderly patients and alcoholics |
| Aspirin, tricyclics, or lithium overdose | Hemodialysis | — |
| Subdural or epidural hematoma | Neurosurgical evaluation for evacuation of hematoma | — |
First-line Agents
Benzodiazepines
Benzodiazepines are the mainstay of abortive treatment of seizures, and the first line in the management of SE. They are the only class 1a level A recommendation in the management of SE, which was supported by a randomized controlled study that found lorazepam more efficacious than phenytoin in controlling SE, and just as efficacious as phenobarbital, or a combination of diazepam and phenytoin, but less cumbersome to use. The most commonly used benzodiazepines in the treatment of SE are diazepam, lorazepam, and midazolam, which are often administered before the patient’s presentation to the hospital by family members or EMS.
Although benzodiazepines are the mainstay of first-line treatment, there are some aspects of each medication that should be considered when approaching a patient with GCSE, because some may be more appropriate than others. Benzodiazepines differ in their time to onset and duration of action, but the most clinically significant difference is the mode of administration and ease of storage ( Table 2 ).
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