Status epilepticus 2013
Treatment of Recurrent Electrographic Nonconvulsive Seizures (TRENdS) Study
Address for correspondence to Aatif M. Husain, 299B Hanes House, 330 Trent Drive, Box 102350, Duke University Medical Center, Durham, NC 27710, U.S.A. E-mail: firstname.lastname@example.org
Nonconvulsive seizures (NCS) and nonconvulsive status epilepticus (NCSE) are electrographic seizures (ESz) that are not associated with overt clinical seizure activity. NCS are distinct ESz, whereas NCSE has ongoing, continuous electrographic seizure activity. Both are common in critically ill patients admitted to hospital intensive care units (ICUs), and studies have shown that about 20% of ICU patients undergoing continuous electroencephalography (cEEG) monitoring will have NCS/NCSE. Although the treatment for convulsive SE is well established, there is no clear consensus for the treatment of NCS/NCSE. Antiepileptic drugs (AEDs), such as phenytoin (PHT) and fosphenytoin (fPHT), used in convulsive SE are also used to treat NCS/NCSE despite lack of data for their appropriateness for these conditions. Recent studies have shown that very aggressive treatment of NCSss/NCSE can lead to worse outcomes because the AEDs used can have significant adverse effects. Recently, several intravenous (IV) AEDs have become available for substitution therapy when their oral use is not possible. There are retrospective case reports and case series that suggest that these AEDs may be beneficial for treatment of NCS/NCSE. The Treatment of Recurrent Electrographic Nonconvulsive Seizures (TRENdS) Study will compare the efficacy and tolerability of fPHT and lacosamide in patients having NCS as noted by cEEG monitoring. The study is currently open to recruitment and has 13 sites in the United States. A total of 200 subjects will be randomized, 100 to each treatment arm.
Nonconvulsive seizures (NCS) are seizures that have only subtle clinical phenomena and alteration of consciousness. Clinical features described with NCS include agitation, facial or limb muscle twitching, nystagmus, sustained eye deviation, catatonia, and psychosis (Husain et al., 2003). NCS are often noted in critically ill patients who are already encephalopathic. In this group of patients, up to 90% of seizures may be nonconvulsive, making their detection difficult (Claassen et al., 2004). NCS are detected with continuous electroencephalography (cEEG) monitoring, and appear as electrographic seizures (ESz; seizures that do not have a clinical correlate). The terms NCS and ESz are used interchangeably when referring to seizures detected on cEEG that do not have an obvious clinical correlate.
Several studies have noted that the frequency of NCS in neurologic intensive care units (NICUs ) and other ICUs is high (Young et al., 1996; Vespa et al., 1999; Claassen et al., 2004). One of the first studies noted that 33.9% of patients undergoing cEEG monitoring in the ICU had ESz, and almost half of them were in nonconvulsive status epilepticus (NCSE; Vespa et al., 1999). More recent studies have noted that about 20% of critically ill patients undergoing cEEG monitoring have electrographic seizures (ESz) (Young et al., 1996; Claassen et al., 2004). After treatment of convulsive seizures, some patients stop having the overt manifestation of seizure activity but continue to have ESz (Delorenzo et al., 1998).
NCS are intermittent, and between seizures the EEG will show variable periods of intervening interictal activity. NCSE, on the other hand, has continuous, ongoing electrographic epileptiform activity. When ESz activity persists for >30 min, it is considered NCSE. Because NCS are intermittent, a 20–30 min EEG may not detect them. Although it is widely believed that cEEG is needed to assess for NCS, there is some uncertainty about how long cEEG monitoring should be continued to exclude the possibility of NCS in comatose patients. One study noted that 95% of patients with NCS had their first seizure within the first 24 h of monitoring (Claassen et al., 2004). However, only 15% of these patients were seizing at the start of the EEG, and only about 50% had their first seizure within the first hour of monitoring. Another area of some uncertainty is how long monitoring should be continued after seizures have been controlled. A recent survey of neurologists who perform cEEG monitoring noted that most respondents (47%) continue monitoring for 24 h after control of seizures (Abend et al., 2010).
Patients noted to be in convulsive SE are aggressively treated with antiepileptic drugs (AEDs) and sedative agents such as pentobarbital. How aggressively NCSE and NCS should be treated is much less clear because the long-term complications of these conditions are not as clear as with convulsive SE. A systematic review comparing treatment of convulsive SE and NCSE with intravenous (IV) AEDs and pentobarbital noted 50% mortality regardless of the treatment (Claassen et al., 2002). Pentobarbital was more effective in stopping the ESz but more often resulted in medical complications such as hypotension, leading to overall comparable mortality. Another study compared treatment of NCSE with IV benzodiazepines in the ICU to less aggressive treatment outside the ICU (Litt et al., 1998). Despite no difference in disease severity, patients receiving benzodiazepines had a higher mortality. The realization that aggressive treatment of NCS with sedative IV medications may be detrimental for patients is reflected in a recent survey of neurologists, which noted much more frequent use of nonsedating AEDs (such as phenytoin [PHT] and levetiracetam) as compared with IV benzodiazepines for the treatment of NCS (Abend et al., 2010).
The Treatment of Recurrent Electrographic Nonconvulsive Seizures (TRENdS) Study is designed to compare the efficacy and tolerability of fosphenytoin (fPHT) and lacosamide (LCM). This study became possible because of the existence the Critical Care EEG Monitoring Research Consortium (CCEMRC). This is a consortium of like-minded investigators and facilities that came together to study EEG patterns in critically ill patients. Members of this consortium have the facility to perform cEEG monitoring in the ICU and have an interest in, among other things, studying the treatment and outcomes of NCS and NCSE.
The largest randomized, double-blind study of convulsive SE demonstrated that lorazepam was more efficacious than phenytoin (PHT) alone in controlling convulsive SE (Treiman et al., 1998). The other two arms of the study, phenobarbital and diazepam followed by PHT, were not significantly different from lorazepam or PHT alone. Because of the sedation and complications associated with IV phenobarbital, it is currently used as a second- or third-line agent. A benzodiazepine followed by PHT is often recommended as the first-line therapy for convulsive SE (Lowenstein & Alldredge, 1998; Drislane, 2000).
Unfortunately there are no randomized, multicenter treatment trials for NCS. Treatment recommendations for convulsive SE are often extrapolated to NCS despite lack of data confirming the appropriateness of this practice. Several studies have shown that aggressive treatment of NCS with sedating AEDs may lead to more complications and worse outcomes than if they were managed less aggressively (Litt et al., 1998; Claassen et al., 2002). fPHT is used in this patient population routinely without data confirming its utility. Small retrospective studies have suggested that the new AED lacosamide (LCM), available in IV formulation, is effective in this patient population (Trinka, 2011; Höfler & Trinka, 2013).
The TRENdS study is a phase II, prospective, multicenter, open-label, randomized study comparing the efficacy of IV LCM with IV fPHT in controlling frequent NCS using cEEG monitoring. The on-site EEG reading physician will interpret the cEEG in real time for treatment purposes, and central reviewers providing final cEEG interpretation for study purposes will review the data at a later date. Both will be blinded to treatment. The treating physician responsible for the clinical care of the subject will not be blinded to treatment.
Clinical Experience with Study Drugs
PHT has been available for several decades. There is extensive experience with the use of PHT in the NICU. The only randomized convulsive SE study, referred to above, confirmed the utility of PHT when combined with a benzodiazepine (Treiman et al., 1998). The IV formulation contains 40% propylene glycol and 10% ethanol to maintain PHT solubility. Extravasation of IV-administered PHT can cause phlebitis and “purple glove syndrome” (Fischer et al., 2003). Other common side effects of PHT include cardiotoxicity, hypotension, hepatotoxicity, leukopenia, thrombocytopenia, pancytopenia, and hepatic enzyme induction (Browne et al., 1996). Despite these complications, PHT has been used as a first-line treatment for seizures and SE in the ICU because of familiarity with the compound and lack of other suitable IV AEDs. With the introduction of fPHT, a water-soluble PHT prodrug, IV administration became safer with a lower risk of phlebitis; however, many of the other complications still persist (Boucher et al., 1996). When used in SE, fPHT is administered as a bolus (“loading dose”) of 18–20 mg phenytoin equivalents (PE)/kg, followed by 5 mg PE/kg/day (Fischer et al., 2003). The efficacy of PHT and fPHT in controlling NCSE or NCS in the ICU is uncertain. There is no large, multicenter trial documenting efficacy of PHT or its superiority to any other AED in this condition.
Adverse events reported with fPHT are similar to those seen with PHT, with nystagmus, dizziness, headache, somnolence, and ataxia being most common. In addition, pruritus is seen more often with fPHT (Knapp & Kugler, 1998). During the infusion, however, the incidence of pain, burning, erythema, tenderness, and swelling is lower with fPHT. In one study, the infusion of PHT had to be slowed or stopped more often than the fPHT infusion (Boucher et al., 1996). Studies have suggested that fPHT is a safer alternative to PHT, and in most situations when IV PHT is needed, fPHT is used. However, a recent white paper commissioned by the U.S. Food and Drug Administration (FDA) noted that the frequency of cardiovascular (arrhythmia and hypotension) and dermatologic (Stevens-Johnson syndrome and pruritus) complications was similar for PHT and fPHT (FDA, 2010).
Lacosamide has undergone three pivotal, double-blind, placebo-controlled trials involving patients with uncontrolled partial-onset seizures (Ben-Menachem et al., 2007; Halasz et al., 2009; Chung, 2010). A total of 1,092 subjects were studied across the three trials. In all studies subjects were started on an LCM dose of 50 mg twice daily and force-titrated to target dose in 6 weeks. Target doses were 200, 400, and 600 mg/day. The pooled analysis of all three trials showed that the percent seizure reduction was 18.4% for placebo, 33.3% for LCM 200 mg/day, and 36.8% for LCM 400 mg/day. The LCM 600 mg/day dose showed a 40% and 38% reduction in seizure frequency in two trials. All three doses were statistically superior to placebo, but there was no significant difference between the 400- and 600-mg/day treatment arms. The 600-mg/day treatment arm had a higher incidence of side effects; therefore, the FDA has approved only the 200- and 400-mg/day doses (Beydoun et al., 2009).
In clinical trials LCM was well tolerated, and most treatment-emergent adverse events (TEAEs) were mild or moderate (Ben-Menachem et al., 2007; Halasz et al., 2009; Chung, 2010). The most common TEAEs were headache, nausea, and dizziness. Discontinuation rates of LCM were 5.2% in the placebo group, 9.6% in the 200-mg/day group, and 17.2% in the 400-mg/day group, and the TEAEs leading to discontinuation were most often dizziness, vomiting, and diplopia. The incidence of rash was not significantly elevated in the LCM arms. Electrocardiographic (ECG) evaluations revealed a slight increase in the PR interval of 1.5 and 3.1 msec in the 200- and 400-mg/day groups, respectively. First-degree atrioventricular (AV) block was noted in three patients, and no patient had second- or third-degree AV block. However, two case reports have noted second- and third-degree heart block in one patient each, the latter with a very high dose of LCM (Krause et al., 2011; Nizam et al., 2011). Hematology and serum chemistry values did not change significantly in the LCM-treated groups (Beydoun et al., 2009).
Bioavailability of IV LCM has been noted to be the same as oral LCM when administered over 30 or 60 min. A multicenter, double-blind, double-dummy, randomized trial of subjects enrolled in an open-label LCM study (patients were already taking LCM) was performed to evaluate the safety and bioavailability of IV LCM 200–600 mg/day (Biton et al., 2008). Thirty minute and 60-min infusions showed bioavailability comparable to oral LCM, and no additional adverse events (AEs) were noted. Specifically no significant ECG changes were noted. A subsequent study evaluated safety of IV LCM boluses of 200, 300, and 400 mg administered over 15 min to outpatient subjects with epilepsy but naive to LCM (Fountain et al., 2013). These subjects were then administered oral LCM 100 mg twice daily, LCM 150 mg twice daily, or LCM 200 mg twice daily for 6.5 days. The percentages of subjects who withdrew from the study due to AEs were 0% for the LCM 200-mg group, 6% for the LCM 300-mg group, and 16% for the LCM 400-mg group. Only one subject had a serious AE (SAE): chest pain. This subject was in the 400-mg group. No ECG changes were reported. A retrospective study done at Duke University Medical Center found that 60% of patients receiving LCM for NCSE or NCS achieved control of their seizures (Doreswamy et al., 2010). Patients with NCS responded more frequently than those who were in NCSE. A recent review of the retrospective use of LCM in treatment of refractory SE showed improvement in 76 (56%) of 136 patients (Höfler & Trinka, 2013). These favorable studies and properties of LCM suggest that it may have a role in patients with frequent NCS.
The primary objective of this study is to evaluate the efficacy of LCM compared with fPHT in the treatment of NCS as measured by cEEG monitoring in critically ill subjects.
The secondary objectives are the following: (1) to evaluate the safety and tolerability of LCM compared with fPHT, and (2) to compare the functional outcomes of subjects treated with LCM compared with fPHT.
All subjects undergoing cEEG monitoring and having ESz will be considered for enrollment. To qualify for randomization, subjects must have at least one ESz lasting at least 10 s, with or without a clinical correlate. If a new AED has been started, the subject must have an ESz after starting that AED.
Subjects will be excluded if they are already being treated with or have a contraindication for the use of one of the study medications. In addition, if the subject is having ongoing generalized convulsive SE or NCSE (defined as at least 30 min of ESz activity per hour of cEEG activity) they will not be eligible for participation. Subjects with generalized absence seizures or absence status epilepticus will not be eligible either. Those subjects admitted for epilepsy surgery evaluation or spell characterization will also not be eligible. Finally, subjects who have ESz following cardiac arrest and anoxic brain injury or those undergoing therapeutic hypothermia are not eligible.
Overview of Study Design
This trial will include a pre–acute-treatment period, an acute-treatment period, a post–acute-treatment period, and a long-term follow-up period. In the pre–acute-treatment period consent for study participation will be obtained, a pregnancy test will be performed on all women of childbearing potential, and the baseline seizure count/frequency will be established. All subjects must be on cEEG monitoring during this period. Subjects will be randomized, and study drug will be administered, marking the beginning of the acute-treatment period.
In the acute-treatment period, cEEG monitoring will be continued, and the primary and most secondary end points will be assessed. Subjects will initially be randomized to either fPHT or LCM. A bolus of fPHT 20 mg PE/kg at a rate not >75 mg PE/min will be used. Subsequent twice-daily maintenance doses will be 2.5 mg PE/kg. Lacosamide will be administered as a bolus of 400 mg IV. The daily maintenance dose will be 200 mg, twice daily. If a breakthrough seizure occurs after the bolus, a rebolus of the same AED will be given. A rebolus of 5 mg PE/kg IV fPHT will be given to subjects receiving fPHT; their daily maintenance dose will be 5 mg PE/kg. A rebolus of 200 mg IV LCM will be given to subjects receiving LCM; as a result of the rebolus, their daily maintenance dose will be 300 mg, twice daily. The acute-treatment phase will end once the subject has not had an ESz 24 h after bolus or rebolus of study medication.
If a seizure occurs within 24 h after a rebolus has been administered, the subject will be crossed over to the second treatment arm. In the second treatment arm, the subject will receive the study drug that was not administered first. The same bolus and rebolus paradigms will be used as were used for the first treatment arm. Once again, the acute treatment phase will end once the subject has not had an ESz 24 h after bolus or rebolus of second study drug. If the subject has a seizure within this time frame, the acute treatment phase will be terminated and the subject treated per best medical practice.
In the post–acute-treatment period, functional outcome will be assessed. Ongoing maintenance AED therapy during the post–acute-treatment period is at the treating physician's discretion, so efficacy of ongoing maintenance AED therapy will not be assessed in this study.
In the long-term follow-up period, subjects or their families will be contacted by telephone at 6, 12, and 24 months postrandomization, to determine if the subject is alive and if so, whether the subject has continued to have seizures since participation in the study and is continuing with AED therapy.
The primary end point will be no recurrence of seizures for 24 h following initial study drug bolus/rebolus with LCM versus fPHT, as measured by cEEG monitoring with blinded review. There are several secondary end points as well, including percentage of subjects who require a second AED to control NCS and functional outcomes.
Current Status of Study
The study is actively recruiting subjects. The TRENdS study is projected to last for another 12–18 months. It will be the first study in which two AEDs have been studied in critically ill patients having NCS using cEEG monitoring as a marker for ESz. Data obtained from this study have the potential to change the current practice of treating acute seizures in critically ill patients.
This study is funded by UCB Pharma through an Investigator Initiated Study grant. The author has received support from, and/or has served as a paid consultant for UCB Pharma, Jazz Pharma, USL, Demos Publishing.
The author receives an unrestricted research grant by UCB. I confirm that I have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.