Medication Summary
Most patients with status epilepticus (SE) who are treated aggressively with a benzodiazepine, fosphenytoin, and/or phenobarbital experience complete cessation of their seizures. If SE does not stop, general anesthesia is indicated. The use of pentobarbital, thiopental, midazolam infusion, propofol, levetiracetam, topiramate, valproate, and inhaled anesthetic agents has been described for this purpose.
Benzodiazepines
Class Summary
These are first-line agents for treating SE. They rapidly achieve therapeutic CNS concentrations after IV administration and act to potentiate action of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS, and rapidly abrogate ongoing seizure activity. Their effect is temporary, which is a limitation; diazepam begins to redistribute out of CNS within minutes. Lorazepam, when available, is thought to be the most effective and has a longer seizure half-life than diazepam. Because the effect is time limited, loading of a traditional AED, such as phenytoin, is recommended soon after administration to help mitigate seizure recurrence.
Lorazepam (Ativan)
Lorazepam is preferred by most neurologists for treatment of SE because of its more prolonged CNS action. It is less fat-soluble than diazepam and therefore takes slightly longer (5-10 min) to stop seizures. It has a smaller volume of distribution than diazepam. Serum concentrations reach 50% of Cmax at 20 min. Lorazepam clears from the brain slower than diazepam but loses protective effect over 30-120 min.
It is important to monitor the patient's blood pressure after administering a dose. Adjust as necessary.
Diazepam (Diastat, Valium)
Diazepam is an extremely lipid-soluble agent that quickly enters the brain in first pass and often stops seizures in 1-2 min. It rapidly distributes to other stores of body fat. Its serum concentration decreases to 20% of maximum concentration (Cmax) 20 min after IV infusion. Individualize dosage and increase cautiously to avoid adverse effects.
Midazolam (Versed)
Midazolam is used as an alternative agent in termination of refractory SE. Because midazolam is water soluble rather than fat soluble, it takes approximately 3 times longer than diazepam to peak EEG effects. Thus, the clinician must wait 2-3 min to fully evaluate sedative effects before repeating a dose.
Anticonvulsant Agents
Class Summary
These agents are used to terminate clinical and electrical seizure activity and to prevent seizure recurrence. Since the full antiepileptic effect of phenytoin, whether given as fosphenytoin or parenteral phenytoin, is not immediate, use of these agents usually follows administration of an IV benzodiazepine.
Phenytoin (Dilantin, Phenytek)
Phenytoin blocks sodium channels in the CNS. It may act in the motor cortex, where it may inhibit spread of seizure activity. The activity of brainstem centers responsible for tonic phase of grand mal seizures also may be inhibited. The dose should be individualized.
A mainstay in the treatment of SE, phenytoin must be administered slowly and takes longer than benzodiazepines to enter the brain. Phenytoin has the advantage of being a long-term anticonvulsant and can be administered orally after acute illness.
Phenytoin is not water soluble, and must be solubilized in propylene glycol carrier with pH 12 to prepare IV. Therefore, the infusion rate is not to exceed 50 mg/min without risk of significant hypotension and cardiac arrhythmias, as well as major risk of potential irritation at IV site and vascular compromise of the infused limb. Therefore, its use in SE should be avoided if possible.
Fosphenytoin (Cerebyx, Sesquient)
Fosphenytoin, a phenytoin prodrug, has similar pharmacologic properties to phenytoin but may be administer more rapidly and has less risk of venous irritation (eg, purple-glove syndrome). It is given IV and requires cardiac monitoring. Avoid IM administration due to delay in onset of action.
Fosphenytoin doses, concentration, and infusion rates are expressed as phenytoin equivalents (PE).
The two brands of fosphenytoin are stored differently. Cerebyx is refrigerated where as Sesquient is stored at room temperature.
Barbiturates
Class Summary
This class of anticonvulsant may be useful when SE fails to respond to phenytoin and benzodiazepines. It is the most commonly used third-line drug, but midazolam, propofol, and others are increasingly used in preference to phenobarbital, although no rigorous evidence supports the use of one third-line drug over another.
Phenobarbital
Phenobarbital works at CNS GABA receptors to potentiate CNS inhibition. It exhibits anticonvulsant activity in anesthetic doses. Phenobarbital is the best-studied barbiturate in treatment of SE.
In SE, achieving therapeutic levels as quickly as possible is important. IV dose may require approximately 15 min to attain peak levels in the brain. To terminate generalized convulsive SE, administer up to 15-20 mg/kg. If the patient has received a benzodiazepine, the potential for respiratory suppression significantly increases. Ventilation and intubation may be necessary. Hypotension may require treatment.
Phenobarbital is generally used after phenytoin or fosphenytoin fails. However, it can be used in lieu of phenytoin in certain circumstances.
If the IM route is chosen, administer this agent into a large muscle such as the gluteus maximus or vastus lateralis or other areas where risk of encountering nerve trunk or major artery is low. Permanent neurologic deficit may result from injection into or near peripheral nerves.
Restrict IV use to conditions in which other routes are not possible, either because patient is unconscious or because prompt action is required.
A trend is to recommend agents other than phenobarbital (propofol, midazolam, other barbiturates) for refractory SE.
Pentobarbital (Nembutal)
A short-acting barbiturate with sedative, hypnotic, and anticonvulsant properties, pentobarbital can produce mood alteration at all levels of CNS. Use only in refractory status when other agents have failed. Patients need intubation and respiratory support.
Anesthetics
Class Summary
These agents stabilize the neuronal membrane so the neuron is less permeable to ions. This prevents the initiation and transmission of nerve impulses, thereby producing the local anesthetic effects. In SE, lidocaine is indicated for refractory cases only and its use is supported only by anecdotal reports. The consensus seems to be moving toward propofol or midazolam infusions for refractory status epilepticus.
Propofol (Diprivan)
A phenolic compound unrelated to other types of anticonvulsants, propofol has general anesthetic properties when administered IV. There are increasing anecdotal reports of its use in refractory status epilepticus. Intubation and ventilation are required. Hypotension may require treatment.
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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.
