Seizures and Status Epilepticus in Adults: Part II
Author: J. Stephen Huff, MD, Associate Professor of Emergency Medicine and Neurology, University of Virginia Health System, Charlottesville, VA.
Peer Reviewers: Andrew D. Perron, MD, Residency Director, Maine Medical Center, Falmouth, ME; and Colleen O. Davis, MD, MPH, FAAP, Associate Professor, Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry, NY.
This issue is the second part of our discussion on status epilepticus in adults. Continued, prolonged seizures are fortunately uncommon, but frightening when they occur. As with other life-threatening conditions where treatment is necessary before full assessment, the author describes how it is important to have an organized and rational approach to treating status epilepticus. The emergency physician should have a memorized approach useful in most patients and one or two alternatives when the primary plan does not work. As with other rare conditions, many of the authoritative recommendations on treating status epilepticus are based on some data but mostly on consensus opinion. Until comparison studies are performed, this article presents the "best evidence" approach to status epilepticus.
J. Stephan Stapczynski, MD, FACEP, Editor
There are a few randomized, blinded, prospective trials for status epilepticus. The most notable is the VA Cooperative Trial, when at time of presentation, patients were randomized into one of four treatment arms: phenobarbital (15 mg/kg); lorazepam (0.1 mg/kg); phenytoin (18 mg/kg); and diazepam (0.15 mg/kg) followed by phenytoin (18 mg/kg). These treatment arms were based on treatment protocols commonly used at the time of study design. EEG was obtained as soon as possible after presentation but did not guide study therapy. There were no significant differences between treatment groups with the exception of the arm of phenytoin alone, which fared the worst of the groups. Another interesting aspect of the study was that slightly less than a third of the patients were found to be in "subtle" generalized convulsive status epilepticus when EEG was promptly obtained.1
The pre-hospital trial for status epilepticus (PHTSE) was unique in that treatment was initiated in the prehospital setting using a shortened time definition of generalized convulsive status epilepticus. Essentially, if seizures were the call to dispatch, and the patient was convulsing on EMS arrival, a diagnosis of status epilepticus was established, and the patients (all adults) were randomized to receive a fixed dose of diazepam (5 mg), lorazepam (2 mg), or placebo. It was concluded that either benzodiazepine was effective and safe in the prehospital environment in the doses used. The study found no significant difference between the treatment arms; nonetheless, the investigators recommended that lorazepam be the drug of choice for prehospital treatment of status epilepticus.2
Step One Therapy Generalized Convulsive Status Epilepticus. There is consensus in the literature that a benzodiazepine should be the first class of drug to treat acute seizures. Benzodiazepines are consistently effective in terminating status epilepticus, are available in most care settings, and depending on the specific medication, may be administered intravenously, intramuscularly, or rectally. Diazepam, midazolam, and lorazepam all have been studied and found effective for treatment of status epilepticus. Studies generally involved fixed dosage regimens, so it is difficult to extrapolate superiority of one drug compared to another when study results may reflect different dose regimens. Respiratory depression is likely related to rate of administration rather than specific effects of any one compound.
EMS care generally parallels ED care with the exception of available medications and issues with route of administration. Diazepam is employed by many EMS systems and is effective. Diazepam may be given intravenously or rectally. Respiratory depression is likely largely related to rate of administration. Lorazepam administration for status epilepticus may cause less respiratory depression resulting in less frequent intubations than diazepam.3 Lorazepam poses particular challenges for implementation in an EMS system because of refrigeration requirements and shortened shelf life if unrefrigerated.
Midazolam has not been the focus of studies as often as other benzodiazepines for initial management of status epilepticus, but is increasingly used for control of generalized convulsive status epilepticus. It may be given intravenously, and unique in this class of medications, is well absorbed when given intramuscularly.4 (See Table 1.) Further discussion of midazolam follows in the section on refractory status epilepticus. A summary of generic and proprietary medication names is listed for convenience in Table 2.
Step Two Therapy Generalized Convulsive Status Epilepticus. Most treatment reviews have listed phenytoin as a second-line drug, with the theory that a longer-acting antiepileptic drug needed to be administered, given the observation of the short anticonvulsant properties of diazepam. Recent reviews offer no change in this recommendation, with the possible substitution of fosphenytoin for phenytoin.
Phenytoin is usually administered by infusion pumps. Rate of infusion should be no faster than 50 mg/min, so loading to the recommended dose in status epilepticus of 20 mg/kg may be lengthy. Hypotension is the most common reason for slowing infusion rates.5 Cardiac monitoring is required since dysrhythmias are reported. Soft-tissue extravasation may lead necrosis, the so-called purple-hand syndrome.6 Largely because of the time required to administer the drug, phenytoin is questioned as an ideal second-line drug.
Fosphenytoin has a phosphate moiety attached to the phenytoin, which greatly increases water solubility. The molar weight is changed as well, and with FDA approval came the recommended dosing in phenytoin equivalents (PE) to simplify clinical operations. The recommended rate of administration is faster than phenytoin at 150 PE/minute with a loading dose of 20 PE/kg.7,8 (See Table 3.) Hypotension is still reported, as are rare arrhythmias. The problem of soft-tissue inflammation is eliminated. Improved water solubility also allows for intramuscular administration with rapid absorption; large IM volumes of 10 cc or more have been studied without adverse effects.9
Refractory Generalized Convulsive Status Epilepticus. The diagnosis of refractory status epilepticusagain the discussion is confined to generalized convulsive status epilepticusis, to a degree, arbitrary. Rather than a time-defined categorization, a better working definition might be an operational definition of seizures that have failed to stop, or that are recurring without the patient returning to full consciousness, after optimal dosing of step 1 and step 2 drugs, that is, after adequate dosages of benzodiazepines and phenytoins. This might occur at several different points in the treatment timeline but current thinking is that the sooner status epilepticus is identified and the sooner treatment is initiated, the more likely status epilepticus will be terminated.
Step Three Therapy Generalized Convulsive Status Epilepticus. (See Table 4.) In the past, the most commonly recommended third-line drug has been phenobarbital, but there is a trend in treatment moving away from this drug to alternatives of midazolam or propofol.10 Again, any recommendations for treatment at this point lack high-level supporting evidence. For generalized convulsive status epilepticus, the recommended dosage of phenobarbital has been 20 mg/kg IV at rates up to 100 mg/minute. Hypotension and respiratory depression may be encountered and require supportive care. Current usage patterns are straying away from use of phenobarbital but admittedly this is largely opinion-driven and without high-level evidence to support changes. Further discussion on barbiturate use in refractory status epilepticus follows in the section below.
The Epilepsy Foundation of America recommendations in a 1993 consensus document included increasing phenytoin to a total loading dose of 30 mg/kg for refractory status epilepticus.11 This was a consensus recommendation without supporting evidence and remains an option in clinical care.
Propofol is readily available in many emergency departments and is often used for procedural sedation because of rapid onset of action. Mechanisms of action include GAGA-A receptor activity. Propofol has been reported to be successful in terminating refractory status epilepticus in small case series and case reports and increasingly is being mentioned in recommendations.12,13 Fewer side effects are reported than with thiopental or other agents.14,15
Dose ranges reported typically recommend an initial bolus dose of 1-2 mg/kg (operationally perhaps an induction dose for intubation), followed by a continuous infusion of 2-10 mg/kg/hr.10 Titration to burst-suppression EEG is recommended when available.14
Cautionary notes have been sounded noting a possible higher mortality with propofol infusions compared to midazolam infusions for refractory status epilepticus in these medically complex patients. The propofol infusion syndrome of metabolic acidosis and collapse is reported with prolonged use of propofol infusions in children.16 There is a call for prospective randomized studies to clarify these issues.17,18
Midazolam is also recommended as a third-line drug for refractory status epilepticus. Continuous IV infusion rates of 0.1-0.6 mg/kg/hour are recommended after a 0.2 mg/kg IV bolus. Less hypotension and ease of titration were reported as advantages.19 Midazolam has been observed to have a prolonged half-life after sustained infusion.20
Critical Supportive Care
Appropriate supportive care will likely be necessary at this juncture. Mechanical ventilation with advanced airway management, namely endotracheal intubation, will be necessary. Intravenous access with multiple lines will likely be necessary for fluid administration, additional medication administration, and possible pressor support.
With the advent of EEG monitoring, discovery is being made of persistent electrical seizure activity in the absence of observable clinical signs. Because of frequent electrographic seizures and even electrographic status epilepticus, some feel that continuous EEG monitoring is essential after an episode of convulsive status epilepticus when the patient has altered mental status.21
There are no studies that systematically look at electrographic monitoring of emergency department patients treated for status epilepticus. Ideally, in the absence of contributing medical conditions, after convulsions have stopped, there should be improvement in mental status within 20 to 30 minutes or so if the patient is not on constant medication infusions. Failure of mental status to improve, or continuing subtle adventitious movements that might represent a forme fruste of convulsions, should prompt consideration of electrographic monitoring to exclude subtle electrographic status epilepticus.
A number of other medications are reported to be of use in generalized convulsive status epilepticus and are included here for completeness without any recommendation for usage. Like the medications above, most are not FDA approved for this indication.
Lidocaine has been proposed as a third-line drug for the treatment of generalized convulsive status epilepticus, but the supporting case series are small. In adults the initial boluses used to stop seizures are 1-3 mg/kg. Constant infusions are usually recommended following termination of up to 3.5 mg/kg/hr.22-24 Recent publications about lidocaine and seizures are in the neonatal and pediatric population.25,26
Valproate is available in the United States in an intravenous formulation and has been regarded as an emerging option for treating status epilepticus.27 Like many other drugs discussed, it does not have a specific FDA approved indication for status epilepticus. High-level evidence for efficacy is lacking, although there are many case reports and case series noting efficacy. Some treatment plans from Europe mention valproate as a third-line option for treatment of status epilepticus.28 Reports also indicate that valproate is often given more rapidly than the FDA-approved rate of 20 mg/min with rates of 6 mg/kg/min reported and loading doses up to 45 mg/kg.27,29 Loading doses are estimated at 25-30 mg/kg body weight.29 To date, head-to-head comparisons of valproate to other medications are limited and the call for additional studies is sounded.27 One study did compare valproate to phenytoin as a second-line drug in the treatment of convulsive status epilepticus. There was a high incidence of symptomatic seizures with CNS infections, stroke, and other structural lesions in the study group. Phenytoin was administered in the standard manner and valproate given as a loading dose at 30 mg/kg infused over 15 minutes with infusion rate kept to 2 mg/kg/min. In this small study in this group, valproate was more effective (66% of status epilepticus terminated) compared to phenytoin (42% terminated). Adverse events were comparable.30
Levetiracetam has recently been released in an FDA approved intravenous formulation. In some intensive care unit settings it is used for off-label indications for seizure prophylaxis and to treat seizures as monotherapy. Usage seems to be as an alternative to phenytoin. Prospective studies evaluating long-term safety, efficacy, and outcomes of this usage are needed.31
Like many other medications, topiramate also has been reported to be useful in cases of refractory status epilepticus. There is no intravenous formulation, so administration must be orally or by nasogastric tube. Effective doses ranged from 300 to 1,600 mg/day.32 As with many of these case series, multiple antiepileptic drugs had been administered, and the patient population was heterogeneous.
Older recommendations tended to include a last-resort recommendation of "general anesthesia," and undoubtedly anecdotal experience was gained as some of these agents were employed as anesthetic therapy. Patients are intubated and receiving mechanical ventilation. Pressors may be required. These have generally been reported in the ICU setting with continuous electrographic monitoring and titration of medications to a burst-suppression EEG pattern.
It is theorized that only patients without underlying brain disease are likely to benefit from prolonged anesthesia to suppress status epilepticus.33 Reported experience with inhaled anesthetics is limited. Logistical issues about delivery of inhaled anesthetics outside the operating room for prolonged periods are noted.34
Barbiturate anesthesia using thiopental or pentobarbital has been reported but problems with hypotension and prolonged recovery are encountered.35,36 Thiopental has been reported to be useful with an initial bolus of 5 mg/kg and repeat boluses of 1-2 mg/kg every 3 to 5 minutes until EEG burst-suppression. Infusions in the range of 5 mg/kg/hr are reported with EEG titration.35
Small cases series of both ketamine and etomidate for refractory status epilepticus exist with initial bolus dosages then infusions. In theory, ketamine is an antagonist at the NMDA subclass of the excitatory neurotransmitter glutamate. Again, cases are complex with many other pharmacologic agents involved.37-39
Many anecdotal and frankly experimental therapies for experimental status epilepticus have been reported. Some reflect experimental animal work while others have been used clinically in a few patients with the usual caveats, i.e., heterogeneous patients, multiple other medications involved, and lack of outcomes data. Some of these studies are summarized for completeness of discussion. Experimentally in an animal model, hypothermia was observed to diminish motor convulsions but not alter epileptic EEG discharges. Diazepam did seem to be effective at a lower dose in this animal model.40 Electroconvulsive therapy has been reported rarely in the treatment of prolonged, refractory status epilepticus.41
What does the future hold? Research in status epilepticus is difficult to conduct because of the sporadic nature of the process, the multifactorial causes, and consent issues. The end-point of seizure controlEEG monitoringis debated as well.
Phenytoin, the consensus second drug recommended for years for treating generalized convulsive status epilepticus, has problems with side effects (frequent hypotension, unusual soft-tissue damage, rare dysrhythmias) and time required for administration. If time is a major factor in terminating status epilepticus and in limiting morbidity, the time of administration may be simply too long. Fosphenytoin solves some of the issues, but is not free of some of the adverse effects of phenytoin.
The role of antiepileptic drugs that have recently been available in intravenous formulation, notably levetiracetam and valproate, remains to be defined in the treatment of generalized convulsive status epilepticus. High-level comparison studies have yet to be constructed.
The role of early electrographic monitoring also has yet to be defined. Although often discussed, practice barriers to obtaining EEG rapidly with interpretation remain. The role of novel EEG technologies remain unclear as well. Ideally, principles of ICU care will be transferred from the neurointensive care units to the emergency department and into prehospital care.
Rather than major changes in drug administration, major changes in recognition and prompt treatment summarizes the newer treatment strategies for status epilepticus. Rapid, optimal benzodiazepine administration, followed with administration of a phenytoin remain the consensus practice at the time of this writing. Beyond these points, there is little consensus other than prompt treatment of the generalized convulsive status epilepticus should occur while investigating etiologies on a priority basis. Propofol and midazolam are assuming prominent roles for treatment of refractory generalized convulsive status epilepticus.
1. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792-798.
2. Lowenstein DH, Alldredge BK, Allen F, et al. The prehospital treatment of status epilepticus (PHTSE) study: Design and methodology. Control Clin Trials 2001;22:290-309.
3. Chiulli DA, Terndrup TE, Kanter RK. The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus. J Emerg Med 1991;9:13-17.
4. Towne AR, DeLorenzo RJ. Use of intramuscular midazolam for status epilepticus. J Emerg Med 1999;17:323-328.
5. Earnest MP, Marx JA, Drury LR. Complications of intravenous phenytoin for acute treatment of seizures. Recommendations for usage. JAMA 1983;249:762-765.
6. O'Brien TJ, Cascino GD, So EL, et al. Incidence and clinical consequence of the purple glove syndrome in patients receiving intravenous phenytoin. Neurology 1998;51:1034-1039.
7. Ramsay RE, DeToledo J. Intravenous administration of fosphenytoin: Options for the management of seizures. Neurology 1996;46(6 Suppl 1):S17-19.
8. Fischer JH, Patel TV, Fischer PA. Fosphenytoin: Clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin Pharmacokinet 2003;42:33-58.
9. Ramsay RE, Wilder BJ, Uthman BM, et al. Intramuscular fosphenytoin (Cerebyx) in patients requiring a loading dose of phenytoin. Epilepsy Res 1997;28:181-187.
10. Alldredge BK, Lowenstein DH. Status epilepticus: new concepts. Curr Opin Neurol 1999;12:183-190.
11. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus. JAMA 1993;270:854-859.
12. Schor NF, Riviello JJ, Jr. Treatment with propofol: The new status quo for status epilepticus? Neurology 2005;65: 506-507.
13. Stecker MM, Kramer TH, Raps EC, et al. Treatment of refractory status epilepticus with propofol: Clinical and pharmacokinetic findings. Epilepsia 1998;39:18-26.
14. Rossetti AO, Reichhart MD, Schaller MD, et al. Propofol treatment of refractory status epilepticus: A study of 31 episodes. Epilepsia 2004;45:757-763.
15. van Gestel JP, Blusse van Oud-Alblas HJ, Malingre M, et al. Propofol and thiopental for refractory status epilepticus in children. Neurology 2005;65:591-592.
16. Vasile B, Rasulo F, Candiani A, et al. The pathophysiology of propofol infusion syndrome: A simple name for a complex syndrome. Intensive Care Med 2003;29:1417-1425.
17. Prasad A, Worrall BB, Bertram EH, et al. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001;42:380-386.
18. Niermeijer JM, Uiterwaal CS, Van Donselaar CA. Propofol in status epilepticus: Little evidence, many dangers? J Neurol 2003;250:1237-1240.
19. Fountain NB, Adams RE. Midazolam treatment of acute and refractory status epilepticus. Clin Neuropharmacol 1999;22: 261-267.
20. Naritoku DK, Sinha S. Prolongation of midazolam half-life after sustained infusion for status epilepticus. Neurology 2000;54:1366-1368.
21. DeLorenzo RJ, Waterhouse EJ, Towne AR, et al. Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia 1998;39:833-840.
22. Walker IA, Slovis CM. Lidocaine in the treatment of status epilepticus. Acad Emerg Med 1997;4:918-922.
23. Aggarwal P, Wali JP. Lidocaine in refractory status epilepticus: A forgotten drug in the emergency department. Am J Emerg Med 1993;11:243-244.
24. Pascual J, Sedano MJ, Polo JM, et al. Intravenous lidocaine for status epilepticus. Epilepsia 1988;29:584-589.
25. Hamano S, Sugiyama N, Yamashita S, et al. Intravenous lidocaine for status epilepticus during childhood. Dev Med Child Neurol 2006;48:220-222.
26. Yamamoto H, Aihara M, Niijima S, et al. Treatments with midazolam and lidocaine for status epilepticus in neonates. Brain Dev 2007;29:559-564.
27. Limdi NA, Shimpi AV, Faught E, et al. Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology 2005;64:353-355.
28. Holtkamp M. The anaesthetic and intensive care of status epilepticus. Curr Opin Neurol 2007;20:188-193.
29. Wheless JW, Vazquez BR, Kanner AM, et al. Rapid infusion with valproate sodium is well tolerated in patients with epilepsy. Neurology 2005:63:1507-1508.
30. Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: A pilot study. Neurology 2006;67: 340-342.
31. Szaflarski JP, Meckler JM, Szaflarski M, et al. Levetiracetam use in critically ill patients. Neurocrit Care 2007;7:140-147.
32. Towne AR, Garnett LK, Waterhouse EJ, et al. The use of topiramate in refractory status epilepticus. Neurology 2003;60: 332-334.
33. Hutchinson M, Swanson PD. Chaos theory and the treatment of refractory status epilepticus: Who benefits from prolonged anesthesia, and is there a better way? Med Hypotheses 2007; 68:439-441.
34. Kofke WA, Snider MT, Young RS, et al. Prolonged low flow isoflurane anesthesia for status epilepticus. Anesthesiology 1985;62:653-656.
35. Parviainen I, Uusaro A, Kalviainen R, et al. High-dose thiopental in the treatment of refractory status epilepticus in intensive care unit. Neurology 2002;59:1249-1251.
36. Osorio I, Reed RC. Treatment of refractory generalized tonic-clonic status epilepticus with pentobarbital anesthesia after high-dose phenytoin. Epilepsia 1989;30:464-471.
37. Sheth RD, Gidal BE. Refractory status epilepticus: response to ketamine. Neurology 1998;51:1765-1766.
38. Nathan BR, Smith TL, Bleck T. The use of ketamine in the treatment of refractory status epilepticus (abstract). Neurology 2002;58 (suppl 3):A197.
39. Yeoman P, Hutchinson A, Byrne A, et al. Etomidate infusions for the control of refractory status epilepticus. Intensive Care Med 1989;15:255-259.
40. Schmitt FC, Buchheim K, Meierkord H, et al. Anticonvulsant properties of hypothermia in experimental status epilepticus. Neurobiol Dis 2006;23:689-696.
41. Carrasco Gonzalez MD, Palomar M, Rovira R. Electroconvulsive therapy for status epilepticus. Ann Intern Med 1997; 127:247-248.
42. Lowenstein DH. The management of refractory status epilepticus: An update. Epilepsia 2006;47 Suppl 1:35-40.
43. Delgado-Escueta AV, Wasterlain C, Treiman DM, et al. Current concepts in neurology: Management of status epilepticus. N Engl J Med 1982;306:1337-1340.