The Management of Refractory Status Epilepticus: An Update

Transcription

1 Epilepsia, 47(Suppl. 1):35 40, 2006 Blackwell Publishing, Inc. C International League Against Epilepsy The Management of Refractory Status Epilepticus: An Update Daniel H. Lowenstein Department of Neurology, University of California, San Francisco, U.S.A. Summary: Refractory status epilepticus (RSE) is an important and serious clinical problem that typically requires prolonged and high-level intensive care, and is often associated with poor outcome. This review addresses some of the current issues concerning the management of RSE, including recent definitions used for clinical studies, epidemiology, clinical course, and outcome. Current approaches to treatment, including the now relatively standard use of intravenous anesthetic agents, as well as emerging therapies utilizing drugs such as valproate and topiramate, are discussed as well. Key Words: Seizures Status epilepticus Antiepileptic drugs. INTRODUCTION Status epilepticus, the condition of ongoing seizures or repetitive seizure activity without a recovery of consciousness between seizures, is a life-threatening emergency affecting between 120,000 and 200,000 people in the U.S.A. annually (1). Numerous studies have documented the morbidity and mortality of status epilepticus, and it is now well-appreciated that the underlying etiology is the predominant, if not primary, factor that determines the outcome (2 7). It is also generally appreciated that a longer duration of status is associated with poorer outcome, even though it is difficult to completely separate out the effects of duration from underlying etiology (4,8). However, a substantial amount of experimental data supports the idea that prolonged seizures cause neuronal injury, and the prevailing clinical practice is to try and abort status epilepticus as quickly as possible (9,10). In addition, there is evidence that the status epilepticus becomes more refractory to treatment with time (11,12). Studies of the initiation of treatment of patients as early as feasible, for example, in the prehospital setting, have demonstrated the benefits of rapid treatment in terms of patient outcomes and minimization of adverse events associated with the therapy itself (13 15). The most common treatment protocols for status epilepticus specify intravenous benzodiazepine (either lorazepam or diazepam) as initial antiepileptic drug (AED) therapy, followed by phenytoin or fosphenytoin and then phenobarbital if seizures continue (9,16 18). Most pa- Address correspondence and reprint requests to Dr. Daniel H. Lowenstein at Box 0114, University of California, San Francisco, San Francisco, CA 94143, U.S.A. lowenstein@medsch.ucsf.edu doi: /j x tients having overt, convulsive status epilepticus respond to the first or second AED (19). However, when the patient fails to respond to this standard, initial treatment, the patient is considered to be refractory and requires additional, more aggressive treatment. This review provides an update on certain aspects of the diagnosis, treatment and outcomes of refractory status epilepticus (RSE). DEFINITIONS AND EPIDEMIOLOGY There is no universally accepted definition of RSE. The various definitions used in the literature rely on specifying either a minimum number of front-line AEDs to which the seizures fail to respond (e.g., two (20 22) or three (9,16,23)), or a minimum duration of seizures that persist despite treatment (e.g., at least one (24) or 2 (20,21) h). The estimates of the frequency of RSE vary from approximately 10 to 40 (3,23,25,26) and rely on clinical series in which there is likely a substantial degree of selection bias and other methodological limitations. Perhaps the best data come from the Veterans Affairs (VA) Cooperative Study on the treatment of generalized convulsive status epilepticus (27). Of 384 patients in overt status epilepticus, 38 failed to respond to the first two AEDs. Furthermore, of 134 patients in subtle status epilepticus (i.e., lacking significant motor manifestations), 82 continued to have seizures after receiving two AEDs (28). Claassen and colleagues have provided the best overview of important epidemiological features of RSE in a systematic review of all the main clinical studies published on the topic through 2001 (29). Their analysis of 28 published reports provided data on 193 patients considered to be in RSE (using the definition of lack of response to at least two standard front-line AEDs). The 35

2 36 D. H. LOWENSTEIN average age of the patients was 48 years, 60 were female, and 34 had a prior history of epilepsy. Eighty-two percent of the patients were in generalized convulsive status epilepticus and 18 were in nonconvulsive status epilepticus. The primary cause of status epilepticus was the following: stroke or CNS tumor (20); epilepsyrelated (20); toxic-metabolic encephalopathy (19); CNS infection (19); hypoxia-ischemia (12), traumatic brain injury (5); and other (6). These general etiological categories are similar to those described in other studies of status epilepticus. COURSE AND OUTCOME Patients in RSE are usually quite ill (substantially more than a typical case of status epilepticus), often with complicated hospital courses and poor outcomes. In a study of 26 episodes of RSE (identified from a consecutive sample of 83 episodes of status epilepticus in 74 patients seen at Columbia University), Mayer et al. found that significant risk factors for developing RSE were nonconvulsive status epilepticus and focal motor seizures at onset (26). Significant complications that occurred more frequently during hospitalization in the RSE patients compared to the non-rse patients in this study included respiratory failure (88 of the 26 episodes), fever (81), pneumonia (65), hypotension (65), bacteremia (46), and the requirement of blood transfusion (50). Similarly, the clinical outcome was worse: mortality was 23 in the RSE cases versus 14 in non-rse cases (although this was not statistically significant), and a reduced Glascow Outcome Scale at discharge was seen in 54 of the RSE cases versus 28 of the non-rse cases. Also, the median duration of time in the neurological intensive care unit (NICU) and the hospital overall was significantly longer in RSE. Increased age and acute symptomatic seizures were associated with mortality, and increased length of hospitalization and acute symptomatic seizures were associated with a poorer level of function in survivors (30). An analysis by Rosetti et al. of 31 RSE episodes in 27 patients yielded similar results in terms of mortality (31). More recently, Holtkamp and colleagues described their experience treating 83 episodes of SE and RSE in the same NICU between 1993 and 2002 (32). They found that encephalitis as an etiology was significantly more associated with RSE than non-rse, and low levels of AEDs in patients with a history of epilepsy was more commonly associated with non-rse. The in-hospital mortality was higher in RSE than non-rse (17 vs. 9), but this was not statistically significant. However, similar to the findings of Mayer et al. (26), RSE patients had a longer length of stay in the NICU and the hospital, and a significantly greater proportion of survivors developed symptomatic epilepsy in the RSE group (88) than the non-rse group (22). These associations, however, were not separable from the potential effects of other factors such as age and etiology. CURRENT THERAPIES Two recent surveys, one primarily based in the United States and the other from Europe, have documented the therapeutic approaches used by specialists treating patients in status epilepticus, and provide insight into the succession of drugs that are typically used as a patient develops RSE. Claassen et al. surveyed 400 randomly selected members of the Epilepsy, Critical Care, and Emergency Neurology sections of the American Academy of Neurology in 2001 (18). The responses of the 106 respondents to a scenario in which a patient requires first- through fourth-line therapy because of ongoing status epilepticus are shown in Fig. 1. The data show that most specialists begin with a benzodiazepine as first-line therapy, and then add fosphenytoin or, less commonly, phenytoin as secondline therapy. There is far less unanimity for the choice of agents for third-line therapy, with 43 of respondents using phenobarbital and 16 using intravenous valproate. However, at this point, many physicians turn to continuous intravenous infusions of pentobarbital, propofol or midazolam, consistent with what has been advocated in the literature (9,12,17,33,34). Holtkamp et al. surveyed 63 neurologists specializing in critical care medicine or epileptology in Austria, Germany, and Switzerland in 2001 and 2002, and focused on the steps taken after failure of first-line drugs (which, for this study, included a benzodiazepine and phenytoin) (35). Approximately two-thirds of the respondents used nonanesthetic AEDs (primarily phenobarbital) as second-line therapy for generalized convulsive status epilepticus, and the remainder turned to a general anesthetic (primarily thiopental, propofol or midazolam) if initial treatment with a benzodiazepine and phenytoin failed. The findings from these two surveys, and the absence of any new consensus report of new protocols, suggest that the most common strategy for treating RSE is to use either pentobarbital (in Europe, thiopentone), propofol or midazolam. Claassen et al s. meta-analysis provided useful information on the relative advantages and disadvantages of these three drugs (29). A summary of the main findings are shown in Fig. 2. Overall, pentobarbital appears to be superior to both propofol and midazolam in effectively controlling RSE (both in terms of stopping seizures at the outset and avoiding breakthrough seizures). However, pentobarbital is significantly more likely to lead to hypotension (defined as a systolic blood pressure of <100 or the need to use vasopressors to stabilize blood pressure). Notably, there was no overall difference in mortality among the three treatment approaches. Two very recent reports have provided additional information regarding the utility of propofol in adult and pediatric cases of RSE. The retrospective study by Rossetti and colleagues (31), which looked at 31 RSE episodes in adults, found that propofol controlled RSE in 67 of cases, and propofol plus thiopental was effective in another

3 MANAGEMENT OF RSE 37 First-line Therapy Lorazepam 81 (76) Diazepam 18 (17) Other 7 (7) Second-line Therapy DPH/FosDPH 101 (95) Other 5 (5) Third-line Therapy Phenobarbital 46 (43) civ-aed 20 (19) Valproate 17 (16) Inc. doses of AEDs 13 (12) Other 10 (9) (n = 5), transient dystonia (n = 1), and transient hyperlipidemmia (n = 1). The authors also noted that none of the deaths in their series could be attributed to the propofol itself. Regarding the pediatric population, van Gestel et al. reviewed their experience treating 33 children (age range 4 months to 15 years) in RSE between 1993 and 2004, a time period during which thiopental was primarily used before 1999 and propofol was the initial treatment after 1999 (36). The authors observed that patients treated with thiopental were less likely to have their RSE brought under control and had a high number of complications. For example, all of the patients required inotropes and extra fluids, and 11 of 20 patients developed pleural effusions. Of greatest concern was the observation that thiopental may have contributed to the deaths of two patients. The authors noted a far more favorable overall course for the majority of patients treated with propofol, and concluded that propofol is preferable to thiopental for RSE in children. However, as with the rest of the literature, this conclusion should be tempered by the fact that the effect of underlying etiology and other uncontrolled factors may explain the differences, a point emphasized in an accompanying editorial (37). Furthermore, in a focused analysis by Niermeijer et al. of 22 articles with original data on the use of propofol in RSE, the authors concluded that there are substantial reasons to be concerned about the safety of propofol in this setting (38) Pentobarbital Propofol Midazolam Phenobarbital Valproate Other Fourth-line Therapy 9 (9) 7 (7) 18 (17) 17 (16) 16 (15) (36) FIG. 1. Preferences for the treatment of status epilepticus based on a survey by Claassen et al. (18) of 106 members of the Critical Care, Epilepsy, or Emergency Neurology sections of the American Academy of Neurology. This is a slight adaptation of the main data figure (Fig. 1) in the original article. Data are shown as number (percent) of respondents. All medications are given as single or repeated intravenous doses, unless otherwise noted. See reference for details of Other in each of the graphs. civ = continuous infusion; AED = antiepileptic drug. Reproduced with permission from reference (18). 10. The median duration of treatment was 3 days (range 1 9 days) and the median ICU stay was 7 days (range 2 42 days). Of the 24 survivors (i.e., representing an overall survival rate of 78), posttreatment complications included shivering (n = 10), mild neuropsychological impairment EMERGING THERAPIES A number of papers have documented the successful use of intravenous valproate in status epilepticus (39 43), and it has been advocated as a first-line agent for absence status epilepticus and a second-line agent for generalized or partial status epilepticus (44). The reports include a mixture of patients treated with intravenous valproate early in the course of status epilepticus and those with RSE, but there are descriptions of patients who appear to have responded very favorably after a lack of response to standard doses of first- and second-line therapy. Particularly impressive was the lack of any serious side effects, most notably cardiovascular side effects, in the great majority of patients. Even more recently, topiramate has been advovated as a potentially useful agent in the treatment of RSE. Towne and colleagues described six adult patients with a variety of forms of status epilepticus who were unresponsive to conventional treatment, including two who also failed to respond to treatment with pentobarbital (45). A suspension of topiramate administered by nasogastric tube was effective in aborting the RSE in all cases. Remarkably, no adverse events were observed and all six patients survived and were discharged from the hospital. Bensalem

4 38 D. H. LOWENSTEIN Midazolam (n=55) Propofol (n=35) Pentobarb (n=106) Total (n=196) Acute treatment failure Breakthrough seizures 51* * 13 Withdrawal seizures Hypotension Requiring Pressors 77* Ultimate Rx failure * Mortality FIG. 2. Treatment responses and outcome of patients with RSE (both convulsive and nonconvulsive) treated with midazolam, propofol, or pentobarbital based on a meta-analysis by Claassen et al. of published studies between 1970 and 2001 (29). Acute treatment failure refers to clinical or electrographic seizures occurring between 1 and 6 h after initiation of intravenous drug. Breakthrough seizures refers to seizures occurring 6 h after the start of therapy. Withdrawal seizures are those occurring within 48 h after tapering or discontinuing treatment. Ultimate treatment failure denotes the need to change to another intravenous drug because the first drug did not sufficiently control seizures. p < = 0.01 Reproduced with permission from reference (29) and Fakhoury also described the use of topiramate via nasogastric tube in three patients with RSE (two with generalized seizures and one with partial seizures) (46). Topiramate appeared to be very effective in aborting RSE that, in two of the patients, was resistant to either pentobarbital or propofol, and no adverse effects were noted. Since topiramate has pleiotrophic effects on neuronal excitability, a favorable pharmacokinetic profile, and appears to have few side effects in the setting of RSE, it is a reasonable therapeutic option. Two additional treatment options deserve note. Inhalational anesthetic agents, which were a common choice for the treatment of RSE prior to the popularization of pentobarbital, propofol, and midazolam, may still have a useful role when other approaches fail. Mirsattari and colleagues recently reported their experience with the use of isoflurane and desflurane in seven RSE patients (ages years) with a variety of seizure types who, in six of the seven cases, did not respond to aggressive therapy with combinations of midazolam, propofol, or pentobarbital (one patient was treated with only midazolam) (47). The authors found that, regardless of the seizure type, the isoflurane and desflurane consistently and immediately suppressed the electrographic seizure activity and induced a sustained burst suppression pattern on the EEG. However, the advantages of the prompt effect and the ease of titration of the agents need to be balanced against their potential adverse effects. All the seven patients developed hypotension and atelectasis, and a subset had infections (n = 5), paralytic ileus (n = 3) or deep venous thrombosis (n = 2). Another treatment option is ketamine, which has been advocated for use in RSE due to its direct action as an excitatory amino acid antagonist (48). In addition to blocking seizure activity, ketamine has a potential neuroprotective effect, and can increase blood pressure due to its sympathomimetic properties. These characteristics make it a reasonable potential choice as adjunctive therapy in RSE, but its clinical use to date appears to be very limited. In an abstract, Bleck and colleagues (49) described their experience with the use of ketamine in seven critically ill patients with RSE. Their main observation was that ketamine produced electrographic seizure control in over half the patients without causing hemodynamic instability. A case report by Sheth and Gidal also provides evidence for the potential utility of ketamine in extremely refractory cases (50). However, another anectdotal report has raised concern about the development of cerebellar toxicity when ketamine is used for prolonged periods (51).

5 MANAGEMENT OF RSE 39 Lorazepam mg/kg IV over 1-2 min (repeat x 1 if no response after 5min) Additional emergent drug therapy may not be required if seizures stop and the etiology of status epilepticus is rapidly corrected. Fosphenytoin 20mg/kg 150mg/min Phenytoin 20mg/kg 50 mg/min Consider valproate 25mg/kg IV in pts. normally taking valproate and who may be subtherapeutic Fosphenytoin 7-10mg/kg 150mg/min Phenytoin 7-10mg/kg 50 mg/min Consider valproate 25mg/kg IV Admit to ICU No immediate access to ICU Phenobarbital 20mg/kg 60mg/min Phenobarbital 10mg/kg 60mg/min IV Anesthesia with Propofol or Midazolam or Pentobarbital* Topiramate mg bid via NGT Consider inhalation anesthesia or ketamine Consider surgical intervention FIG. 3. Treatment protocol for status epilepticus based on current literature. See reference (17) for details concerning loading and maintenance doses of drugs where not specified in the figure. All the agents used for refractory RSE have the potential for very significant side effects (see text) and should be used only by physicians with expertise in this setting. Maintenance doses of phenytoin and other first- or second-line agents are typically continued concurrent with third-line agents. Pentobarbital may be preferable for patients who are young and have no cardiovascular risk factors. IV, intravenous; NGT, nasogastric tube. CONCLUSIONS RSE is a dangerous and challenging clinical entity that accounts for a substantial proportion of the poor outcomes and more complex care associated with status epilepticus. Treatment approaches to RSE continue to evolve, but there is currently no evidence to show the superiority of any one of the many protocols being used by experienced specialists in this field. A suggested protocol that takes into account a number of observations in the literature is shown in Fig. 3. Given the experimental and clinical data suggesting that prompt intervention is an important determinant of treatment response in aborting prolonged seizures, the best hope for dealing with RSE is to prevent its development in the first place through the use of potent drugs early in the course of status epilepticus. REFERENCES 1. DeLorenzo R, Hauser W, Towne A, et al. A prospective, populationbased epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46: Aminoff M, Simon R. Status epilepticus: causes, clinical features and consequences in 98 patients. Am J Med 1980;69: Lowenstein D, Alldredge B. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43: Towne A, Pellock J, Ko D, DeLorenzo R. Determinants of mortality in status epilepticus. Epilepsia 1994;35: DeLorenzo R, Pellock J, Towne A, Boggs J. Epidemiology of status epilepticus. J Clin Neurophysiol 1995;12: Walker M. The epidemiology and management of status epilepticus. Curr Opin Neurol 1998;11: Alldredge B, Lowenstein D. Status epilepticus: new concepts. Curr Opin Neurol 1999;12: Alldredge B, Lowenstein D, Simon R. Status epilepticus in the 1980s: etiology, treatment and outcome. Neurology 1990;40(suppl. 1): Lowenstein D, Alldredge B. Current concepts: status epilepticus. N Eng J Med 1998;338: Lowenstein D, Bleck T, Macdonald R. It s time to revise the definition of status epilepticus. Epilepsia 1999;40: Lothman E. The biochemical basis and pathophysiology of status epilepticus. Neurology 1990;40 (suppl. 2): Shorvon S. The management of status epilepticus. J Neurol Neurosurg Psychiatry 2001;70(suppl. 2):II Cloyd JC, Lalonde RL, Beniak TE, Novack GD. A single-blind, crossover comparison of the pharmacokinetics and cognitive effects of a new diazepam rectal gel with intravenous diazepam. Epilepsia 1998;39:520 6.

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