Approach Considerations
Both generalized tonic-clonic status epilepticus (SE) and subtle SE must be treated aggressively. Maintenance of vital signs, including respiratory function, is of major importance. Any indication of respiratory insufficiency should be addressed by intubation.
Early treatment measures are performed in concert with diagnostic studies. The treating physician should not wait for a blood level to return from a laboratory test before giving the patient a loading dose of phenytoin. The same protocol should be followed regardless of whether the patient is already taking phenytoin. Assume that the patient is noncompliant because this is the most common cause of SE in patients with known epilepsy.
Even if the patient has been compliant and even if phenytoin levels were already in the therapeutic range (10-20 µg/mL), data suggest that 20-30 µg/mL is more effective than 10-20 µg/mL in stopping seizures.
High doses can cause ataxia and sedation. Because the patient is likely to be hospitalized after the SE is controlled, these adverse effects are less important than they would be in a patient being treated on an outpatient basis. SE is a life-threatening situation, and the patient will be admitted to the hospital after treatment. Therefore, if treatment errs, it should err on the side of excessive medication. Temporary adverse effects are preferred to irreversible brain damage or death.
Finally, systemic acidosis is not a major concern because it is usually transient, and medical treatment to normalize acidosis can lead to a rebound metabolic alkalosis when the SE stops. In addition, evidence suggests that acidosis has antiseizure effects.
The approach to treatment of motor focal SE—specifically, epilepsy partialis continua—is similar to that with generalized convulsive SE. However, the urgency of treatment and the extremes to which a physician may elect to go to terminate the seizure are tempered.
The basic principles of emergency care (ie, attention to airway, breathing, and circulation [ABCs] apply to focal as well as to generalized SE. Although generalized convulsive SE frequently jeopardizes the ABCs, epilepsy partialis continua only infrequently does so.
See the image below for management algorithms for convulsive status epilepticus.
Treatment Guidelines
In 2016, the American Epilepsy Society (AES) issued new guidelines for the treatment of SE. The guidelines provide a time-dependent treatment algorithm that includes four phases. [62]
In the stabilization phase, standard first-aid for seizures should be initiated.
In the initial therapy phase, a benzodiazepine (specifically IM midazolam, IV lorazepam, or IV diazepam) is recommended as initial therapy.
In the second phase, options include IV fosphenytoin, valproic acid, or levetiracetam. If none of these is available, IV phenobarbital is a reasonable alternative.
In the third phase, if a patient experiences 40+ minutes of seizure activity, treatment considerations should include repeating second-line therapy or anesthetic doses of thiopental, midazolam, pentobarbital, or propofol.
Prehospital Care
Supportive care, including ABCs, must be addressed in the prehospital setting. If the seizure fails to stop within 4-5 minutes or if the patient is continuing to seize at the time of emergency medical system (EMS) personnel arrival, prompt administration of anticonvulsants may be necessary.
Because of the refrigeration requirements and the infrequent use of most anticonvulsants, diazepam (Valium) is often the only anticonvulsant available in the prehospital setting. Diazepam may be administered intravenously (IV) or per rectum. Midazolam (Versed) is available in some EMS systems and is currently the subject of study because of the option for intramuscular and intranasal administration.
If persons who know the patient, or who witnessed the onset of the seizures, are present at the scene, EMS providers may be able to collect information that offers clues to the cause of the SE.
Emergency Department Care
Regardless of the clinical manifestations of generalized SE, aggressive supportive care and prompt termination of electrical seizure activity are the goals. Care is individualized to the patient.
Establish intravenous access, ideally in a large vein. Intravenous administration is the preferred route for anticonvulsant administration because it allows therapeutic levels to be attained more rapidly. Begin cardiac and other hemodynamic monitoring.
Administer a 50-mL bolus of 50% dextrose IV and 100 mg of thiamine. If seizure activity does not terminate within 4-5 minutes, start anticonvulsant medication. If EMS history has already defined SE, treatment should begin immediately. In some settings where drug intoxication might be likely, consider also adding naloxone at 0.4-2.0 mg IV to the dextrose bag.
Administer diazepam (0.15 mg/kg) or lorazepam (0.1 mg/kg) IV over 5 minutes, followed by fosphenytoin or phenytoin. Fosphenytoin is preferable, as it provides the advantage of a potentially rapid rate of administration with less risk of venous irritation (eg, to avoid the risk of purple-glove syndrome with phenytoin).
Fosphenytoin is given in a dose of 15-20 mg phenytoin equivalents [PE]/kg, at a rate not to exceed 150 mg PE/min). The dose of phenytoin is 18-20 mg/kg, at a rate not to exceed 50 mg/min). Never mix phenytoin with a 5% dextrose solution; put it in a normal saline solution to minimize the risk of crystal precipitation.
Ensure airway control. Nasopharyngeal airway placement is sufficient for some patients, particularly if the seizures are stopped and the patient is awakening. For other patients, endotracheal intubation is necessary. In neuromuscular paralysis, rapid sequence induction is necessary at times. Use short-acting paralytics to ensure that ongoing seizure activity is not masked. Use EEG monitoring if long-acting paralytics are used and if a question exists about seizure cessation.
Correct any metabolic imbalances. Control hyperthermia.
If seizures continue after 20 minutes, give additional fosphenytoin (10 mg PE/kg IV) or phenytoin (10 mg/kg IV). Aim for a total serum phenytoin level of about 22-25 µg/mL.
In patients with epilepsy partialis continua who had been receiving AED treatment, knowledge of the patient's usual regimen and current levels may be pivotal. As an alternative to fosphenytoin or phenytoin, supplementation of their routine medication (guided by stat AED levels) may help suppress their seizures.
Failure to respond to optimal benzodiazepine and phenytoin loading operationally defines refractory status epilepticus. If seizures continue after 20 minutes, give phenobarbital (15 mg/kg IV). Use caution when adding barbiturates to benzodiazepines because their coadministration may potentiate ventilatory failure. This may be especially true for patients (eg, elderly patients) with impaired drug clearance.
For this reason, especially in the setting of partially treated epilepsy partialis continua or simple partial SE, in which the morbidity of the underlying illness is less than in generalized convulsive SE, a tempered approach may be preferred. Incremental doses of phenobarbital may offer satisfactory efficacy in these uncommon settings and may be safer than full intravenous loading doses, which increase the risk of respiratory suppression.
Alternatives to phenobarbital that are shorter acting and allow for periodic neurologic assessments include the following [63, 64] :
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Valproate
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Levetiracetam
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Midazolam
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Pentobarbital
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Ketamine [67] }
If seizures continue, consider administering general anesthesia with medications such as propofol, midazolam, or pentobarbital. Ketamine infusion can alternatively (or additionally) be used in the treatment of refractory status epilepticus, with some evidence of safety and efficacy. These agents are given by IV drip and titrated to a burst-suppression pattern in the EEG trace. In a patient with epilepsy partialis continua or simple partial SE, one might even consider rapid oral loading of one of the newer AEDs (eg, topiramate [68] ), depending on the ongoing clinical urgency. Lacosamide is a novel antiepileptic drug available in IV form; though anecdotally it appears safe, its effectiveness in treatment of refractory SE is unknown.
If the patient promptly becomes alert after receiving a benzodiazepine or other AED, that tends to corroborate the diagnosis of SE. Nevertheless, the failure to become alert by no means excludes the diagnosis of SE. Most patients remain sleepy or stuporous after the resolution of a prolonged episode of SE, whether focal or generalized.
For this reason, bedside EEG assessment can be invaluable in guiding treatment decisions. This is true not only early in the treatment paradigm but also late to help gauge the patient's recovery and to ensure that he or she is not having repeated subclinical seizures. Portable computer-aided EEG monitoring (LTM system) can be particularly helpful in this task.
Antiepileptic Drug Selection
Benzodiazepines are the preferred first-line agents. According to 2016 guidelines from the American Epilepsy Society (AES), any of three benzodiazepines — intramuscular (IM) midazolam, intravenous (IV) lorazepam, or IV diazepam — should be given if first-aid stabilization measures don't stop the seizure within 5 minutes. [62] Although diazepam is familiar to paramedics and emergency physicians, a consensus has evolved among neurologists and epileptologists that lorazepam may be preferred in this setting because of its long distribution half-life.
A comparison of initial IV treatment for overt generalized convulsive SE by Treiman et al found that lorazepam was more effective than phenytoin alone. [41] Lorazepam was not more effective than phenobarbital or diazepam plus phenytoin, but it was easier to use. Not studied was fosphenytoin, which is theoretically a significant improvement over phenytoin.
A 2014 Cochrane Database review found intravenous lorazepam is better than intravenous diazepam or intravenous phenytoin alone for cessation of seizures. [69]
Intravenous valproic acid has been shown in a pilot study to be equal to or better than phenytoin in aborting generalized SE, and it has been used in some cases of focal status epilepticus. [70, 71]
The use of levetiracetam (Keppra) in treatment of refractory SE has been examined, in part due to its availability in intravenous form, although its use in treating focal SE remains investigational. [72, 73, 74] Anecdotal reports describe the beneficial use of topiramate in some cases of focal SE.
There are several intravenous formulations of antiepileptic drugs (AEDs) at different stages of development. [75] Some of these might be able to help refractory cases with SE as adjunctive therapy.
No data clearly support a best third-line drug. Controlled trials are lacking, and recommendations vary greatly. While phenobarbital has historically been among the most widely used, the list of third-line drugs also includes intravenous agents such as midazolam, propofol, pentobarbital, valproate, levetiracetam, lidocaine, [76] , ketamine [67] } and others. Lacosamide, a novel antiepileptic drug available for intravenous injection, may be used safely as adjunctive therapy for SE, but little data exist on its efficacy. [77]
A clinical practice trend seems to be for use of propofol as a third-line agent, often initiated during induction for endotracheal intubation. However, propofol infusion syndrome and increased mortality is reported when used at high doses and for prolonged periods. [66]
Absence status epilepticus
Benzodiazepines and valproate are the treatments of choice for absence SE. Valproic acid is available in intravenous (IV) form. The theoretical advantage is that it can be continued long term after the acute episode. Valproate is loaded at a dose of 25 mg/kg IV in a 50-mL solution and infused over 10 minutes. The next dose is given 3 hours later, after which every-6-hour dosing can be started. The drug should never be given intramuscularly. Ethosuximide also can be useful, but is not available in parenteral form.
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Treatment algorithms for convulsive status epilepticus.
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Focal status epilepticus. Electroencephalograph (EEG) in a patient with epilepsia partialis continua caused by Rasmussen encephalitis before hemispherectomy. The patient had long-standing, intractable partial epilepsy since the first decade of life. Seizures included complex partial with occasional secondary generalization and repetitive myoclonus involving the left side of the body. Note the frequent epileptiform discharges at 1-2 Hz involving the right frontocentral channels. These were evident on many of the patient's routine EEGs. Clinical myoclonus is often correlated with high-voltage bursts of such activity.
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Focal status epilepticus. Electroencephalograph (EEG) in a 35-year-old patient with a history of intractable partial epilepsy, in complex partial status epilepticus. The patient underwent a rapid antiepileptic drug taper as an inpatient for long-term video/EEG monitoring as a presurgical candidate. On clinical observation, the patient abruptly stopped and stared, exhibiting automatisms. This first of 2 EEG fragments covers approximately 30 seconds and illustrates the start and evolution of a seizure in the right temporal lobe. The onset appears to be at Sp2 and T4. Note the time of the event, 18:35 on May 9.
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Focal status epilepticus. This electroencephalographic (EEG) fragment was obtained at approximately 12:39 on May 10, 18 hours after the onset of complex partial status epilepticus originating in the right temporal lobe, in a 35-year-old patient with a history of intractable partial epilepsy. Other EEG acquisitions over the interval were identical. On clinical observation, the patient was lethargic, sluggish, and vague, with variable responsivity to examiners. Note the persistent epileptiform discharges at 1.5-2.5 Hz with phase reversal mainly at Sp2 though infrequently shifting to Sp1 and F7. The bulk of the discharges are maximal at Sp2, reflecting their mesial temporal origin, with rare, subtle, and low-amplitude reflection from lateral neocortical channels (F8). Background activities are slow with admixed beta frequencies. This finding corresponds to complex partial status epilepticus.
