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Status epilepticus (SE) is one of the most frequent neurological emergencies with an incidence of 20/100,000 per year and a mortality between 3% and 40% depending on etiology, age, SE type and duration. Generalized convulsive forms of SE (GTCSE), in particular, require aggressive treatment. Presently, only 55–80% of cases of GTCSE are controlled by initial therapy. Therefore, there is a need for new options for the treatment of SE. Here we review the current standard treatment including recent advances and provide a summary of preclinical and clinical data regarding treatment options which may become available in the near future. The initial treatment of SE usually consists of a benzodiazepine (preferably lorazepam 0.1 mg/kg) followed by phenytoin or fosphenytoin or valproic acid (where approved for SE therapy). With intravenous formulations of levetiracetam, available since 2006, and lacosamide, which is expected for autumn of 2008, new treatment options have become available, that should be evaluated in prospective controlled trials. If SE remains refractory, the induction of general anaesthesia using propofol, midazolam, thiopental, or pentobarbital is warranted in GTCSE.
Status epilepticus (SE) is one of the major neurological emergencies with an incidence of about 20/100,000 for the causasian population in industrialized countries [Chin et al. 2006; Vignatelli et al. 2005, 2003; Knake et al. 2001; Coeytaux et al. 2000; Jallon et al. 1999]. SE has usually been defined as a single clinical seizure lasting more than 30 min or repeated seizures over a period of more than 30min without intervening recovery of consciousness [Knake et al. 2001; DeLorenzo et al. 1995; Epilepsy Foundation of America's Working Group, 1993; Hauser, 1990].
However, in clinical practice, a generalized tonic-clonic seizure lasting for more than 5–10 min would usually be considered as SE and should be treated as such [Lowenstein and Alldredge, 1998, 1993]. The etiology of SE is heterogeneous and age dependent. The most common causes in children are febrile seizures or infections with fever, accounting for more than 52% of all pediatric cases. Remote symptomatic causes and low antiepileptic drug (AED) levels also account for a significant percentage of cases in children. A much different picture emerges in the adult population. The major causes are remote symptomatic causes such as acute cerebrovascular accidents, hypoxia, metabolic causes and low AED levels [Knake et al. 2001; Hesdorffer et al. 1998; DeLorenzo et al. 1995].
SE is associated with short-term case fatality rates of around 20% (3–39%) [Rosenow et al. 2007; Vignatelli et al. 2003; Wu et al. 2002; Rosenow et al. 2002; Knake et al. 2001; Tomson, 2000; Kaplan, 2000; Fountain, 2000; Coeytaux et al. 2000; Lowenstein and Alldredge, 1998; Hesdorffer et al. 1998; Logroscino et al. 1997; DeLorenzo et al. 1995; Hauser, 1990]. Main predictors of case fatality are age, the etiology of SE (especially anoxia), severity of the underlying disease and the duration of SE [Garzon et al. 2003; Wu et al. 2002; Lowenstein and Alldredge, 1998; Towne et al. 1994; Hauser, 1990;]. Patients over the age of 60 with a severe underlying disease (such as acute stroke or anoxia) have the highest risk of SE-associated mortality. Effective treatment should be initiated as soon as possible in patients with SE.
There are a number of different national and European guidelines for the treatment of SE [Minicucci et al. 2006; Meierkord et al. 2006; Epilepsy Foundation of America's Working Group, 1993]. The main aims of treatment are (a) to support vital functions, (b) to identify and treat causal or precipitating factors, and (c) to terminate ictal activity. The first priority is to ensure that the airways are clear and that vital functions are maintained. Cardio-respiratory function should be checked and oxygen administered (6 l /min). Intravenous (IV) access should be established so that blood can be taken to determine levels of glucose, electrolytes and drugs, to check liver and kidney function, and blood count and to give the anticonvulsant of choice. The aggressiveness of therapy and the drug chosen for treatment after a benzodiazepine (preferably lorazepam (LZP)) is given as first-line treatment depends on the SE type (e.g., generalized tonic clonic vs absence SE), the age, the comorbidity and the prognosis of the patient. Before IV treatment is initiated the differential diagnosis, especially the possibility of psychogenic or hypoglycemic status, should be considered.
Out of hospital: There is evidence that the administration of rectal diazepam (DZP) by trained lay persons, is effective in the control of acute repetitive seizures [Dreifuss et al. 1998]. A prospective, randomized, placebo-controlled study of GTCSE showed that the out-of-hospital use of benzodiazepines by paramedics was superior to placebo [Alldredge et al. 2001]. LZP (2 mg), DZP (5mg), or placebo were initially given. A second identical dose was administered if convulsions continued after four minutes. SE was terminated on admission to the hospital in 59.9% of cases treated with LZP, in 42.6% of those treated with DZP, and in 21.1% of the patients treated with placebo. Complications (hypotension, cardiac arrhythmia, and need for respiratory support) were less frequent in the LZP (10.6%) and DZP (10.3%) groups as compared to the placebo group (22.5%). Furthermore, short-term case fatality rates were lower in the benzodiazepine-groups (LZP: 7.7%, DZP: 4.5%) compared to placebo (15.7%). It had previously been shown by the same group that the probability to control GTCSE with initial therapy decreases with increasing SE-duration at initiation of therapy [Lowenstein and Alldredge, 1993]. If treatment was initiated within one hour, the control rate was approximately 80%. If therapy was started two hours or more after the onset, the control rate dropped to only 40–50%. In conclusion, in GTCSE a sufficient dose of a benzodiazepine (preferably 2–4mg of LZP) should be given as soon as possible by trained paramedics or emergency doctors. Unfortunately, despite existing evidence, LZP is not approved for the treatment of SE in many countries.
Once the patient is admitted, LZP should be given IV up to a total dose of 0.1 mg/kg, considering doses/timing of benzodiazepines already given out of hospital (5mg DZP is equivalent to 1mg LZP). It is probably less important to consider previously administered midazolam because of its short half-life. Several studies including the one by Alldredge et al.  (described in the section above) have compared LZP to DZP in the treatment of SE. Leppik et al.  compared LZP and DZP in 79 patients with 81 episodes of different types of SE. LZP was effective in 89% of the episodes, and DZP in 76% – a nonsignificant but potentially relevant difference. The time to onset of action and the frequency of adverse events was similar in both groups. LZP has been found to be nonsignificantly superior in each of the available comparative studies; a recent Cochrane review including eleven studies on SE concluded that LZP was superior to DZP or phenytoin in the initial treatment of established SE [Prasad et al. 2005]. Because LZP is less lipophilic, it has a smaller volume of distribution and a longer distribution half-life (12 h) than DZP (15–30 min), and therefore a potentially longer anticonvulsive effect [Treiman et al. 1998; Greenblatt and Divoll, 1983]. Soluble preparations of LZP need to be stored cooled, which is a practical disadvantage. However, efficacy can be maintained for at least three days if not sufficiently cooled [Alldredge et al. 2001].
Traditionally, the initial rapidly acting benzodiazepine was followed by a dose of 18mg/kg of IV phenytoin given at a maximal infusion rate of 50 mg/minute [Delgado-Escueta et al. 1982]. Only relatively recently a controlled study investigating the treatment of GTCSE addressed the treatment options on arrival at hospital [Treiman et al. 1998]. The authors divided GTCSE in two groups: ‘overt SE’ (with clearly visible convulsions) and ‘subtle SE’ (with only subtle motor manifestations as a sequel of electromechanic decoupling, usually occurring in the later stages of GTCSE). They compared the SE control rates 20 min after initiation of four different therapies: DZP (0.15mg/kg) followed by phenytoin (18 mg/ kg); LZP (0.1 mg/kg); phenobarbital (15 mg/kg); or phenytoin (18 mg/kg) alone. Overt SE was controlled within 20 min after initiation of therapy with LZP in 64.9% as compared to DZP followed by phenytoin (55.8%), phenobarbital (58.2%) and phenytoin alone (42.6%). The only treatment significantly worse than LZP alone was phenytoin alone. Interestingly, phenobarbital was most effective in the smaller group of patients with subtle SE – with low control rates of 24.2% as compared to 17.9 (LZP), 8.3% (DZP plus phenytoin), and 7.7% (phenytoin alone). The frequency of hypotension and respiratory insufficiency was similar across the groups [Treiman et al. 1998].
Phenytoin solution can lead to severe tissue damage, especially if injected paravenously [Rao et al. 1988; Kilarski et al. 1984]. Due to its very alkaline pH of 12, even IV application can result in phlebitis and, in more severe cases, the so called ‘purple glove syndrome’ in at least 1.5% of patients [Burneo et al. 2001; O'Brien et al. 1998; Jamerson et al. 1994]. Fosphenytoin is a disodium phosphate ester of 3-hydroxymethyl-5,5 diphenylhydantoin, which is rapidly and completely converted to phenytoin (conversion half-life 8–15 min). The ready-mixed solution is buffered to a pH of 8.6–9 and can be given IVor intramuscularly (IM). However, IM application is not recommended during SE, because absorption is unreliable and may take more time. Local toxicity is clearly decreased compared to phenytoin [Ramsay et al. 1995; Jamerson et al. 1994]. Fosphenytoin is given at a rate of 100–150 mg/ min, compared to 50mg/min for phenytoin. However, maximal plasma concentrations achieved are approximately 15% lower than with phenytoin [Browne et al. 1996; Eldon and Loewen, 1993], and in rats, the brain tissue concentrations reached with fosphenytoin are lower than those achieved using equivalent doses of phenytoin [Walton et al. 1999]. In conclusion, fosphenytoin is preferable to phenytoin for IV use.
If possible and especially when there is delayed recovery, clinical treatment success should be confirmed by EEG because it has been reported that up to14% of patients treated for GTCSE remain in nonconvulsive SE after the convulsions are clinically controlled [DeLorenzo et al. 1998] Table 1.
Refractory status epilepticus (RSE) is defined as SE that has failed to respond to first and second-line anticonvulsant drugs [Bleck, 2005; Claassen et al. 2002; Treiman et al. 1998; Bleck, 1993] and occurs in up to 44% of all patients with SE [Stecker et al. 1998; Lowenstein and Alldredge 1998; Krishnamurthy and Drislane, 1996; Yaffe and Lowenstein, 1993]. The mortality of RSE is at least 16–23% and again depends on age and etiology [Rossetti et al. 2005; Holtkamp et al. 2005; Claassen et al. 2002; Mayer et al. 2002]. Its treatment remains a challenge and has not been investigated in prospective trials so far. In general, RSE is treated with coma induction using anesthetics such as propofol, or midazolam or barbiturates (pentobarbital or thiopental).
A meta-analysis on the treatment of 193 patients with RSE that were treated with pentobarbital, propofol, or midazolam suggested that pentobarbital was superior regarding treatment success and prevention of breakthrough seizures but was associated with more side effects such as hypotension. There was no difference between all three agents in terms of short-term case fatality, which was between 40% and 50% [Claassen et al. 2002]. Other anesthetics, such as isoflurane, ketamine, or lidocaine have been used in single patients and may be an option if SE remains refractory [Rossetti, 2007; Mirsattari et al. 2004; Sheth and Gidal, 1998].
Valproic acid has been used IV in SE for more than 20 years; however, only one randomized study has been performed comparing phenytoin alone (an inferior treatment) against valproate, but without a conclusive statistical difference (one-sided t-tests were used) [Misra et al. 2006]. Despite the lack of good class I evidence, IV valproate (ivVPA) has recently been approved for the treatment of SE in Norway (in 2004) for SE, in adults and Germany (in 2007) as third choice drug for generalized convulsive SE, as second choice for simple and complex partial SE and as a first choice in absence SE. The approval was based on more than 300 ‘well-documented’ cases of SE treated with ivVPA published in a number of case series [Olsen et al. 2007; Velioglu and Gazioglu, 2007; Limdi et al. 2005; Uberall et al. 2000; Sinha and Naritoku, 2000; Venkataraman and Wheless, 1999; Czapinski and Terczynski, 1998], the interaction, especially with phenobarbital, and the rare occurrences of pancreatitis are problematic [Grosse et al. 1999]. Furthermore, VPA should not be administered to patients with mitochondrial disease or severe liver disease [Uusimaa et al. 2008; Rosenow et al. 2002].
After a long interval during which many novel AEDs reached the market but were not made available for IV use, IV levetiracteam was approved in 2006 for patients who cannot take their medication orally. In 2008, lacosamide will be the first AED to be approved simultaneously as an oral and IV formulation. Both compounds will not be approved for the use in SE.
Levetiracetam (LEV) is a SV2A-ligand and inhibits high-voltage-gated calcium currents, selectively involving the N-type-calcium channels [Lukyanetz et al. 2002]. LEV has been studied in several animal models of SE. Animal studies support the anticonvulsive effect of LEV in SE showing that LEV prevented, diminished or aborted seizures in rats with self-sustained SE and that LEV may enhance the effect of benzodiazepines [Mazarati et al. 2004]. However, other groups could not confirm the anticonvulsive effect in rats during SE but suggested neuroprotective properties of LEV. In a rat model of self-sustaining limbic SE after two hours of stimulation of the perforant path, LEV administration did not terminate seizures or have any significant effect on spike frequency but improved biochemical function, indicating that LEV might protect against mitochondrial dysfunction during SE in rats [Gibbs and Cock, 2007; Gibbs et al. 2006].
In healthy humans, bioequivalence of oral and IV administered doses of 1500–4000mg LEV has been shown [Ramael et al. 2006a, b]. A steady state was reached after 48h for oral and IV application [Ramael et al. 2006a]. Rapid infusion rates of up to 4000 mg/15 min or 2500 mg/5 min have been well tolerated, with few and minor side effects affecting the central nervous system such as somnolence or dizziness. No serious adverse events occurred [Ramael et al. 2006a, b].
Clinical data on the treatment of SE in humans are sparse: there are a few case reports [Schulze-Bonhage et al. 2007] and one small clinical series [Knake et al. 2008] on the treatment of SE with IV LEV. Data so far suggest that LEV may be an effective and well-tolerated treatment for SE. However, LEV is not approved for the treatment of SE and further prospective controlled evaluation in a larger number of patients is warranted.
Lacosamide (LCM) selectively affects sodium channel slow but not fast inactivation and so reduces the long-term availability of sodium channels. Furthermore, it modulates the collapsin response mediator protein 2 (CRMP-2). It is currently not clear if this mode of action contributes to the anticonvulsive effects of LCM [Doty et al. 2007]. Lacosamide has been studied in different SE models. In self-sustained SE evoked by 60 min of electrical stimulation of the perforant path, LCM (50mg/kg) was compared to DZP (10 mg/kg), phenytoin (50 mg/kg), and vehicle. Drugs were injected 10min after the end of the stimulation and all reduced seizure duration and time to last seizure significantly compared to vehicle, LCM was most effective [Stohr et al. 2006]. In a second study, LCM was injected 10 min after the initiation of the status by electrical stimulation of 30 min duration. LCM significantly reduced neuronal loss in CA1 and CA3 as compared to vehicle [Stohr and Wasterlain, 2006]. Furthermore, LCM showed efficacy in two models of chemically-induced SE. In the cobalt/homocysteine-induced model, LCM protected against GTC seizures and in the lithium chloride/pilocarpine model neuroprotective effects were seen [Stohr et al. 2007; Bialer et al. 2007; Stohr et al. 2003].
In probands, bioequivalence with regards to the oral application was demonstrated after injection of 200mg over 15, 30, or 60min. Sleepiness, dizziness, and perioral hypesthesia were the most common adverse events. An initial IV replacement trial in 60 patients showed that LCM was well tolerated when given over 30 or 60min [Biton et al. 2008]. Subsequently, during a phase 3 extension study (SP755) 160 patients with focal epilepsy received IV replacement of their oral dose, usually 400–600 mg/day (200–800 mg). The daily dose was given in two doses administered within 10, 15, or 30min. Headache occurring in 5–8%, dizziness in 5–8%, somnolence 0–10%, and diplopia (0–5%) were the most frequent adverse events. One serious adverse event, a bradycardia of 4min duration, occurred during the second but not first 15-min infusion, and was interpreted to be caused by a vasovagal event (Krauss et al. 2007). It was concluded that the IV application was dose-equivalent and of similar tolerability to the oral formulation [Doty et al. 2007].
Based on these data, LCM is certainly a promising candidate for clinical evaluation in the treatment of SE.
The lack of evidence from controlled double blind trials of SE treatment has several reasons: (a) it is usually not possible to obtain informed consent, which under the current EU directive (2001/20/EC, 4.4.2001) renders it practically impossible to include patients in the European Union; (b) the potential economic gain for the pharmaceutical industry from developing drugs for SE is low, even though the impact of SE on the population is substantial; (c) SE is an emergency situation with little time to establish even the diagnosis and underlying aetiology, and treatment is frequently initiated outside the hospital; (d) Current treatment controls GTCSE in 64– 80% of cases [Misra et al. 2006; Treiman, 1998]. In order to demonstrate that a new drug is 10% more effective or equally effective as current standard treatment, more than 800 patients would need to be included. Should these problems be overcome, a trial design should consider: (a) a prospective randomized assignment to treatment groups; (b) double-blind parallel group designs, and (c) unambiguous operational definitions of SE and treatment success. EEG monitoring is important in this respect. Patients with generalized tonic clonic SE, complex partial SE, and simple partial SE with motor signs should be included in such a trial, using a stratified randomization procedure. Patients with absence status and simple partial status without motor signs should be excluded. Since the study by Alldredge et al., it is clear that LZP is more efficacious and safer than placebo and the trial by Treiman et al. demonstrated that there are three equally effective standard treatments. Therefore, placebo groups are no longer ethically acceptable, every patient included needs to receive one of these standard treatments [Alldredge et al. 2001; Treiman, 1998; Treiman et al. 1998]. For a life-threatening disorder such as SE a 10% improvement in success rate or clear demonstration of noninferiority for substances that are better tolerated (e.g., fosphenytoin or valproate vs phenytoin) would be clinically meaningful. Such results need to be supported with substantial statistical power [Treiman, 1998]. Therefore, in future studies, no more than two treatment arms should be compared. One possibility would be LZP plus either fosphenytoin or a new agent (e.g., LCM or LEV).
Felix Rosenow, Interdisciplinary Epilepsy Center Marburg Department of Neurology Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35033 Marburg, Germany.
Susanne Knake, Interdisciplinary Epilepsy Center Marburg Department of Neurology Philipps-University Marburg, Marburg Germany.