Treatment of Convulsive and Nonconvulsive Status Epilepticus Trudy Pang, MD Lawrence J. Hirsch, MD* Address * Comprehensive Epilepsy Center, Columbia University, Neurological Institute, Box NI-135, 710 W. 168th Street, New York, NY 10032, USA. E-mail:
[email protected] Current Treatment Options in Neurology 2005, 7:247–259 Current Science Inc. ISSN 1092-8480 Copyright © 2005 by Current Science Inc.
Opinion statement Status epilepticus (SE) should be treated as quickly as possible with full doses of medications as detailed in a written hospital protocol. Lorazepam is the drug of choice for initial treatment. If intravenous access is not immediately available, then rectal diazepam or nasal or buccal midazolam should be given. Prehospital treatment of seizures by emergency personnel is effective and safe, and may prevent cases of refractory SE. Home treatment of prolonged seizures or clusters with buccal, nasal, or rectal benzodiazepines should be considered for all at-risk patients. Nonconvulsive SE is underdiagnosed. An electroencephalogram should be obtained immediately in anyone with unexplained alteration of behavior or mental status and after convulsive SE if the patient does not rapidly awaken. Delay in diagnosis of SE is associated with a worse outcome and a higher likelihood of poor response to treatment. For refractory SE, continuous intravenous midazolam and propofol (alone or in combination) are rapidly effective. Randomized trials are needed to determine the best treatment for SE after lorazepam.
Introduction Status epilepticus (SE) is a medical and neurologic emergency. Overall, mortality is approximately 17% to 23% [1,2]. An additional 10% to 23% of patients who survive SE are left with new or disabling neurologic deficits [2,3]. The varied presentation of nonconvulsive SE (NCSE) can lead to misdiagnosis or delayed treatment. This article will review the recent literature pertaining to early, efficient recognition and management of SE.
DEFINITION AND CLASSIFICATION Status epilepticus has traditionally been defined as continuous or repetitive seizure activity persisting for at least 30 minutes without recovery of consciousness between attacks [4]. Recent revisions of this definition gradually shortened the duration of SE. Because isolated seizures rarely last more than 5 minutes, the current operational definition of SE is 5 minutes or more of continuous seizures or two or more discrete seizures with incomplete recovery of consciousness between sei-
zures [5]. From a clinical standpoint, the most practical definition is any patient who is still seizing. There are many different types of SE. The simplest classification scheme divides SE into two major types: convulsive and nonconvulsive, based on whether or not there is rhythmic jerking. Generalized convulsive status epilepticus (GCSE), including generalized tonic-clonic, myoclonic, tonic, and clonic, is more easily recognized than NCSE. However, as GCSE continues, the overt symptoms usually evolve into subtler features, such as subtle twitching of the face or limbs, or nystagmus [6]. Some patients may not show any motor symptoms of seizure and therefore have nonconvulsive status epilepticus. It is this group of patients who often evade early diagnosis because NCSE has protean manifestations, ranging from slight alteration of consciousness to coma. In the intensive care unit (ICU), most seizures are nonconvulsive and would not be noticed without electroencephalography (EEG) [7••]. Some clinicians attempt to classify NCSE
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based on its site of onset; however, practically, it often is not possible to distinguish between NCSE of generalized onset and NCSE of partial onset with bilateral spread.
ETIOLOGY The most frequent cause of SE is a prior history of epilepsy (22% to 26%). However, more than half of episodes of SE occur in patients without prior seizures. In these patients, stroke (19% to 20%) is the most frequent cause, followed by remote causes (16%), toxicmetabolic encephalopathy (12% to 18%), alcohol and/or drugs (8% to 15%), tumor (4% to 20%), cardiac arrest or hypoxia-ischemia (4% to 12%), infection of the central nervous system (CNS) or other infection (4% to 7%), traumatic brain injury (2% to 5%), and idiopathic or unknown causes (2% to 15%) [2;8, Class III; 9]. Metabolic etiologies include: low glucose, calcium, sodium, magnesium and phosphate (the latter particularly in alcoholic patients); high glucose, osmolality, blood urea nitrogen or creatinine; medication toxicity (theophylline, imipenem, isoniazid [treat with pyridoxine], clozapine, cyclosporine a n d r e l a t e d d r u g s, f e n t a ny l , m e p e r i d i n e, p r o poxyphene, bupropion, and high dose intravenous [IV] beta-lactam antibiotics); withdrawal from medications and drugs (benzodiazepines, barbiturates, alcohol); and acute intoxication from illicit drugs, especially cocaine.
DIAGNOSIS OF STATUS EPILEPTICUS AND NONCONVULSIVE STATUS EPILEPTICUS Early recognition of SE allows for prompt treatment and increases the likelihood of treatment success. Typically, patients who present with GCSE are expected to awaken gradually after the motor features of seizures disappear. If the mental status remains depressed 20 to 60 minutes after the convulsions cease, NCSE must be considered and urgent EEG is advised.
Nonconvulsive seizures and NCSE are much more common than previously recognized, particularly in patients who are in the intensive care unit. Risk factors for nonconvulsive seizures or NCSE include severely impaired mental status of any cause, young age (90%). Phenytoin may displace other drugs that are protein-bound and increase free levels of other drugs. Also induces hepatic metabolism of many medications, including other AEDs. Main side effects Cardiac arrhythmias (bradycardia, ectopic beats), hypotension, hepatotoxicity, pancytopenia, phlebitis, soft tissue injury from extravasation, purple glove syndrome, allergy including Stevens-Johnson syndrome. Special points During and after SE, the target free-phenytoin level should be 1.5 to 2.5 g/mL, equivalent to a total phenytoin level of 15 to 25 g/mL in the presence of normal protein binding. Daily serum levels should be followed. Free phenytoin levels can become very high in patients with low albumin (malnutrition, critical illness, liver insufficiency) or those who are on other highly protein-bound drugs such as benzodiazepines and valproate. It cannot be mixed with glucose or dextrose because of precipitation and should not be given in small peripheral veins or IM.
Fosphenytoin
Standard dosage
Contraindications Main drug interactions Main side effects
Special points
Fosphenytoin is a phenytoin prodrug without the propylene glycol carrier and has fewer side effects. It is quickly dephosphorylated to phenytoin when given IM or IV. IV fosphenytoin is preferred to IV phenytoin because of its water solubility and normal pH, thereby allowing more rapid administration with less irritation of veins, less hypotension during administration, no risk of skin necrosis or purple glove syndrome with extravasation, and compatibility with all IV fluids. It is dosed as phenytoin-equivalents. 20 mg/kg load given intravenously. The maximum infusion rate is 150 mg/min (three times the rate of phenytoin). If patients continue to seize after receiving 20 mg/kg, an additional 5 to 10 mg/kg may be given. It also can be given intramuscularly, with low therapeutic levels reached in 30 minutes and peak levels in 2 hours, but this is too slow for convulsive SE. The elimination half-life is 10 to 15 minutes (for conversion to phenytoin). See phenytoin. See phenytoin. Lower risk of hypotension than phenytoin (5% to 15%, rate dependent). Arrhythmias and respiratory depression are rare. Decreased consciousness, transient pruritus (in as many as 50% of awake patients, not an allergic reaction; often in the groin; possibly attributable to phosphate load) also are possible. Cardiac complications still can occur with fosphenytoin. Blood pressure and electrocardiograms should be monitored well after infusion ends because phenytoin is effectively still being loaded for more than 15 minutes after the end of the infusion. Otherwise the side effects are the same as phenytoin. See phenytoin for target serum levels. Serum phenytoin levels should be obtained 2 hours after an IV load or 4 hours after IM delivery to allow complete conversion to phenytoin.
Phenobarbital
Standard dosage Contraindications Main drug interactions Main side effects Special points
Phenobarbital is one of the long acting barbiturates that act by potentiation of ␥aminobutyric acid (GABA) and by interfering with sodium and potassium transport across the cell membrane. 15 to 20 mg/kg given intravenously. The maximum infusion rate is 50 to 100 mg/ min. The elimination half life is 72 hours. Hypersensitivity to drug, severe liver dysfunction. Increased respiratory depression, sedation, and hypotension are possible, especially when given in conjunction with benzodiazepines. Respiratory depression (patients often need intubation), prolonged sedation, allergy including Stevens-Johnson syndrome, blood dyscrasias. Target serum levels are 30 to 45 g/mL initially, but some patients may need higher levels.
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Valproate
Standard dosage
Contraindications Major drug interactions
Main side effects Special points
Although currently not approved by the United States Food and Drug Administration for use in SE, several small case series suggest good efficacy for IV valproate in the treatment of different types of SE, including partial onset, nonconvulsive, absence, and myoclonic SE [35,36]. In a recent review of 63 patients, IV valproate was infused at an average dose of 31.5 mg/kg (range, 10 to 78 mg/kg), an average rate of 200 mg/min (range, 200 to 500 mg/min) [37]. An overall efficacy of 63.3% was achieved when used as a second, third, or fourth drug. It was well-tolerated with hypotension occurring in only three patients. 20 mg/kg load given intravenously; however, in the presence of enzyme-inducing drugs such as phenytoin, phenobarbital, or carbamazepine, higher dosages of 40 to 60 mg/kg are needed. Maximum bolus rate: approved for rates up to 3 mg/kg/min for a total loading dose of up to 15 mg/kg (although we and others give much larger loading dosages as above). Faster rates have been well-tolerated, including 5 to 6 mg/kg/min [35,38]. Hypersensitivity to drug, severe liver dysfunction, thrombocytopenia. Because of the interaction between phenytoin and valproic acid, which are heavily protein-bound AEDs, it is important to follow unbound (free) levels, especially of phenytoin, to avoid toxicity. Hepatotoxicity (including fatal), thrombocytopenia, pancreatitis. Hypotension is rare but has been reported [39]. Target serum levels are 70 to 140 g/mL for SE. There is minimal sedation (intubation may be avoided); therefore, it is particularly useful for refractory SE in a patient who has a “do not intubate” status.
Comparison of initial treatment options for status epilepticus • Only a few prospective randomized trials have been done comparing treatment strategies for SE; some were discussed above. The largest prospective study was the VA Status Epilepticus Cooperative study [33••, Class I], which was a randomized, double-blind, multicenter trial that compared four IV treatments: lorazepam, diazepam followed by phenytoin, phenobarbital, and phenytoin alone. In generalized convulsive SE, lorazepam was found to be most effective (65% for lorazepam alone vs 58% for phenobarbital, 56% for diazepam plus phenytoin, and 44% for phenytoin alone). The difference was statistically significant between lorazepam and phenytoin only. For subtle SE, no statistical difference was found between the groups and the response rate was poor. All four treatment arms had similar complication rates.
Refractory status epilepticus • Refractory SE (RSE) is defined as persistent convulsive SE or NCSE despite the use of two agents (usually a benzodiazepine plus another drug, typically phenytoin). The next step of treatment usually is use of continuous drips or high doses of medications that may cause significant sedation, respiratory depression, and hypotension. Patients most often at this point have been intubated and transferred to the intensive care unit. The available agents include barbiturates (pentobarbital, thiopental, or high dose phenobarbital), propofol, and midazolam. The traditional treatment algorithm suggests loading with phenobarbital at this point, followed by continuous IV pentobarbital if that fails. Our preference is to use rapid-acting drips (midazolam or propofol) instead of phenobarbital after a patient has failed first- and second-line drugs.
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Epilepsy • To date, no randomized controlled trials have been done for second-line therapy or for SE refractory to first- and second-line therapy. The most experience exists with continuous infusions (cIV) of midazolam and propofol. There is some preliminary evidence from two small retrospective series that propofol is effective, fast, and easy to use [40,41, Class III], but may be associated with a higher mortality than midazolam (but not statistically different). In a systematic review of the literature on treatment of 193 patients with RSE, no difference was found in mortality among the groups treated with cIV propofol, cIV midazolam, or cIV pentobarbital [42, Class III]. Mortality was related to the patient’s age and duration of SE rather than AED choice. The safety of propofol was additionally supported in a more recent retrospective series by Rossetti et al. [43•, Class III], in which 27 patients who failed IV clonazepam and phenytoin therapy were induced into burst-suppression pattern on cEEG with cIV propofol at a dose of 2.1 to 13 mg/kg/h for 1 to 9 days while continuing clonazepam infusions. Seven deaths (23%) were reported but none were attributable directly to propofol use and no patient experienced propofol infusion syndrome. A systematic review by Claassen et al. [42, Class III] (published before the Rossetti propofol study) found no demonstrable difference between propofol and midazolam for clinical endpoints such as acute treatment failure, breakthrough seizures, or posttreatment seizures. Pentobarbital seemed to have had a lower frequency of acute treatment failure and breakthrough seizures, but this was confounded by two factors. First, the pentobarbital was infused until background burst suppression was reached, whereas the other two drugs usually were titrated to seizure control, not burst-suppression. Second, most patients on pentobarbital did not have continuous EEG monitoring. In our experience and others, most breakthrough seizures in RSE patients are subclinical (89%), and would be missed in the absence of continuous EEG monitoring [31, Class II; 44•, Class III]. Hypotension, which further complicates the treatment of these critically ill patients, occurred more frequently with pentobarbital (titrated to EEG background suppression) than with propofol or midazolam (usually titrated to suppression of seizures) [42, Class III].
Continuous intravenous antiepileptics for refractory status epilepticus in adults • All patients on cIV AEDs require continuous EEG monitoring.
Continuous intravenous pentobarbital Standard dosage 5 to 10 mg/kg bolus. Repeat 5 mg/kg boluses until seizures stop. Maximum bolus rate is 25 to 50 mg/min (if blood pressure permits). The initial infusion rate is 1 mg/kg/h. The usual maintenance range is 0.5 to 10 mg/kg/h, traditionally titrated to suppression-burst on EEG. The elimination half life is 15 to 60 hours. Contraindication Hypersensitivity to drug. Main side effects Prolonged coma (usually days after infusion is stopped), hypotension (usually requires vasopressors), myocardial depression, immune suppression, ileus, allergy including Stevens-Johnson syndrome.
Continuous intravenous midazolam Standard dosage 0.2 mg/kg bolus. Repeat 0.2 to 0.4 mg/kg boluses every 5 minutes until seizures stop, up to a maximum total loading dose of 2 mg/kg. The initial infusion rate is 0.1 mg/kg/h. The usual maintenance range is 0.05 to 2 mg/kg/h (this is higher than dosages in older literature). For breakthrough seizures, an additional bolus can be given, and the cIV rate should be increased by 20%. SE usually stops in less
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than 1 hour. Duration of antiepileptic effects is minutes to hours. The elimination half-life is 1.5 to 3.5 hours initially. With prolonged use, there may be tolerance, tachyphylaxis, and significant prolongation of half-life, up to days [45]. Contraindications Hypersensitivity to drug. Main side effects Sedation of minutes to several hours and possibly days with prolonged use, respiratory depression, occasional hypotension.
Continuous intravenous propofol
Starting dosage
Contraindications Main side effects
Special points
Propofol is a GABA-A agonist that suppresses seizure activity via GABA-mediated inhibition of neuronal firing. Other mechanisms of action include inhibition of the N-methyl-D-aspartate receptor and modulation of calcium influx through slow calcium ion channels. 1 mg/kg bolus. Repeat 1 to 2 mg/kg boluses every 3 to 5 minutes until seizures stop, up to maximum loading dose of 10 mg/kg. Initial cIV rate is 2 mg/kg/h. Continuous IV dosage range is 1 to 15 mg/kg/h. SE usually stops in less than 10 minutes. Hypersensitivity to drug; allergy to soybean oil, egg lecithin, or glycerol. Sedation lasting 5 to 10 minutes, large lipid load (3000 cal/d) requiring adjustment of caloric intake, occasional pancreatitis, dose-dependent hypotension, rare propofol infusion syndrome (metabolic acidosis and circulatory collapse). Multiorgan failure in children has been reported with prolonged use [46]. The use of propofol in adults at these dosages for less than 2 weeks with close monitoring including acid/base status seems to be safe and effective based on recent data and from the experience of many centers anecdotally.
Treatment algorithm for convulsive status epilepticus • Based on the results of the VA study, IV lorazepam is the preferred first-line therapy. Although second-line therapy has not been prospectively evaluated, phenytoin or fosphenytoin are most frequently recommended. Patient who do not have success after trials with two AEDs are said to have RSE, which is very difficult to control. In the VA Cooperative Study [33••, Class I], of the 38% of patients with "overt" SE and the 82% of patients with "subtle" SE that continued to seize after receiving two AEDs, 2% and 5%, respectively, stopped seizing after receiving a third agent. Additionally, only 5% of patients responded to phenytoin as a second-line agent after lorazepam failed. Therefore, some epileptologists recommend progressing directly to anesthetic drips after lorazepam has failed. See Table 1 for our SE treatment protocol for adults.
Tapering continuous intravenous antiepileptic drugs • In all patients treated with continuous infusions, AED drips should be continued for at least 24 hours after cessation of seizures to avoid relapse [42, Class III]. The infusions can then usually be tapered over 24 hours. If seizures recur during the taper, resume the prior effective dose. On the subsequent attempt, reduce the drip more slowly while maintaining high therapeutic levels of other AEDs such as phenytoin.
Adjunctive enteral medications • Antiepileptic drugs that are only available in oral form, including levetiracetam, topiramate, gabapentin, oxcarbazepine, and carbamazepine, can be given via nasogastric tubes or percutaneous enterogastrostomy tubes in conjunction with IV treatments for SE. These medications may be useful adjuncts in preventing breakthrough and withdrawal seizures, especially in
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Other pharmacotherapy for refractory status epilepticus Ketamine There is some experimental evidence that the initial stages of SE are best stopped with GABA agonists such as benzodiazepines and barbiturates, but prolonged RSE becomes resistant to this treatment and is better treated with antiglutamate agents [49]. Ketamine, an NMDA antagonist, has been used for prolonged SE with some success, although there is very little literature in humans. Borris et al. [50] showed that ketamine was ineffective in early status, but very effective in prolonged status, and may have neuroprotective properties. Neurotoxicity has been reported from high-dose ketamine; therefore, routine or prolonged use can not be recommended without additional studies.
High-dose phenobarbital There is some evidence, primarily in children, that very high-dose phenobarbital, with serum levels 100 to 300 g/mL, can be effective treatment for refractory SE. Crawford et al. [51, Class III] used this approach in 50 children younger than age 13 years, and found that phenobarbital is many times more potent than pentobarbital or thiopental in its anticonvulsant properties relative to its CNS depressant effects. Many patients regained consciousness despite high levels.
Other medications Thiopental, lorazepam and diazepam continuous infusions, lidocaine, etomidate, isoflurane, paraldehyde, electroconvulsive therapy, transcranial magnetic stimulation, and neurosurgery [52, Class III], also have been used in RSE. More recently, there has been success with use of topiramate in RSE [53, Class III].
Pediatric considerations • The general principles of management and the initial agents used in the pediatric population remain the same (see Table 1). Again SE refers to seizures lasting longer than 5 minutes. Based on the consensus guidelines produced by the Status Epilepticus Working Party of the British Pediatric Neurology Association [54], the initial drug of choice is IV lorazepam when an IV is available. It should be given at a dosage of 0.1 mg/kg over 30 to 60 seconds, and may be repeated once after 5 minutes if necessary. If IV access cannot be established or if the child is in an out-of-hospital setting, rectal diazepam 0.6 mg/kg should be given. Seizures that persist despite the above treatment require phenytoin loading at 20 mg/kg or phenobarbital loading at 20 mg/kg if the patient already has been given phenytoin. Intensive care monitoring is required at this point, and urgent continuous EEG monitoring should be obtained. If SE is refractory to the above treatments, the British guidelines call for rapid sequence anesthesia induction using IV barbiturates (thiopentone at 4 mg/kg). In our experience, refractory SE in
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children also can be treated effectively with cIV midazolam. Unlike adults, cIV propofol is a poor option attributable to the risk of multi-organ failure. IV valproate is best avoided in children younger than 2 years because of the risk of fulminant hepatitis, especially with polypharmacy.
Emerging therapies • Effective treatment of SE can only begin with early and efficient diagnosis. Delays in treatment are associated with poorer prognosis [8, Class]. With NCSE occurring in as many as 34% of neurologic intensive care patients [55], 16% of severe head trauma patients [56], and 8% of comatose patients that have no clinical evidence of seizures [32•], early recognition and treatment of the condition will make a huge impact on the outcome of these patients. • Lorazepam is an excellent and proven first-line treatment of SE; however, optimal treatment beyond benzodiazepines is less certain. Particularly in RSE, randomized trials to compare the efficacy of various continuous AED infusions are needed, with clearer definitions of the goal of treatment based on EEG. As mentioned earlier, alternative routes of benzodiazepine administration also need to be studied for treatment of out-of-hospital acute repetitive seizures or SE. Nasal or buccal midazolam looks promising in this regard. • Neuroprotection is a key area of future research in the management of SE, both to prevent neuronal injury associated with SE, and to potentially prevent epileptogenesis. Animal models will continue to play an important role in our exploration of various agents, including the newer AEDs, glutamate receptor antagonists, calcium channel blockers, antioxidants, erythropoietin, and hypothermia. • Identifying a reliable neuronal injury marker will also be helpful in guiding treatment. DeGiorgio et al. [,]5857 suggest that neuron-specific enolase, or NSE, may be that marker of neuronal injury as it correlates with the duration of SE and outcome. Additional work in this area is needed. • Complementary to laboratory investigations are the various imaging modalities during and after SE, such as magnetic resonance imaging with diffusion-weighted imaging (often shows focal bright signal during and after SE), functional magnetic resonance imaging, positron emission tomography, single photon emission computed tomography, and magnetic resonance spectroscopy (e.g. for lactate); microdialysis also may play an important role. These techniques may help us to better understand the pathophysiology of SE and guide us in its treatment.
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