Abstract
Kumar S, Ramanuiam B, Chandra PS, Dash D, Mehta S, Anubha S, Appukutan R, Rana MK, Tripathi M. Epilepsia 2018;59:460–467.
OBJECTIVE: Antiepileptic drugs (AEDs) are routinely withdrawn during long-term video-electroencephalography (EEG) monitoring (LTM), to record sufficient number of seizures. The efficacy of rapid and slow AED taper has never been compared in a randomized control trial (RCT), which was the objective of this study. METHODS: In this open-label RCT, patients aged 2–80 years with drug-resistant epilepsy (DRE) were randomly assigned (1:1) to rapid and slow AED taper groups. Outcome assessor was blinded to the allocation arms. Daily AED dose reduction was 30% to 50% and 15% to <30% in the rapid and slow taper groups, respectively. The primary outcome was difference in mean duration of LTM between the rapid and slow AED taper groups. Secondary outcomes included diagnostic yield, secondary generalized tonic-clonic seizure (GTCS), 4- and 24-hour seizure clusters, status epilepticus, and need for midazolam rescue treatment. The study was registered with Clinical Trial Registry-India (CTRI/2016/08/007207). RESULTS: One hundred forty patients were randomly assigned to rapid (n = 70) or slow taper groups (n = 70), between June 13, 2016 and February 20, 2017. The difference in mean LTM duration between the rapid and slow taper groups was −1.8 days (95% confidence interval [CI] −2.9 to −0.8, P = .0006). Of the secondary outcome measures, time to first seizure (2.9 ± 1.7 and 4.6 ± 3.0 days in the rapid and slow taper groups respectively, P = .0002) and occurrence of 4-hour seizure clusters (11.9% and 2.9% in the rapid and slow taper groups, respectively, P = .04) were statistically significant. None of the other safety variables were different between the 2 groups. LTM diagnostic yield was 95.7% and 97.1%, in rapid and slow taper groups respectively (P = .46). SIGNIFICANCE: Rapid AED tapering has the advantage of significantly reducing LTM duration over slow tapering, without any serious adverse events
Commentary
The epilepsy monitoring unit (EMU) is designed to facilitate definitive diagnosis of seizures and determine candidacy for escalation of treatment for drug resistant epilepsy (DRE) such as surgical resection. In the EMU, seizures are regularly provoked by antiepileptic drug (AED) reduction with precautions to quickly rescue unintended prolonged or generalized seizures in order to avoid harm or intensification of care. Despite management by experienced clinicians, there have been adverse events including deaths from sudden unexpected death in epilepsy (SUDEP) captured in the EMU (1). The process of removing medications to provoke seizures is largely accomplished through common sense decision making on the part of the responsible neurologist based on how frequent and how major the seizures are, which has been supported by expert consensus (2). The National Association of Epilepsy Centers (NAEC) now requires accredited centers to establish protocols, because using a protocol has been shown to be safer than not using a protocol to limit seizure clustering and status epilepticus (3). However, there are currently no guidelines to inform us on how to proceed in this somewhat risky business to create our protocols (4). Even the new SUDEP guideline (5) offers no recommendations with regard to minimizing risk of tapering AEDs in the EMU (6).
A recent study by Kumar and colleagues set out to provide information to address efficient and safe tapering of AEDs for patients with drug-resistant epilepsy brought to the EMU for seizure capture. They designed an open-label randomized controlled trial for patients aged 2- to 80-years old who had never had status epilepticus (SE), had fewer than daily seizures, and had therapeutic AED levels on arrival to the EMU. They randomized patients with DRE to fast taper (30–50% reduction) or slow taper (15–30% reduction) of AEDs in succession. The primary outcome for which the study was powered, duration of long-term monitoring (LTM) until adequate seizures were captured, was significantly shorter (1.8 days) for patients randomized to the rapid taper group. For secondary outcomes, rapid taper group had shorter time to first seizure, but a greater number of 4-hour seizure clusters. There were no other significant differences in safety in the two groups, including use of rescue medications. Outcomes were assessed in a blinded manner. These results led the researchers to conclude that rapid tapering in the EMU is safe and efficient for patients with DRE, something important for their center in India where there are substantial waits for LTM.
A recent study (7) showed that rapid AED tapering was associated with longer EMU admissions and longer time to first seizure, seemingly a jarring finding until scrutinizing the difference in methods essential in comparing the two studies. Physicians selected more rapid withdrawal AED tapers (>50% reduction of AEDs) and more complete withdrawal of AEDs for patients with infrequent seizures in order to capture seizures in this retrospective and observational study (8). It becomes less surprising that it took longer to achieve the goals of LTM because of the bias built into the methodology.
There are some limitations in the Kumar et al. study. Because this was a single site, relatively small, open-label design, the generalizability to all EMUs is diminished. The tapering schedule for the rapid taper group overlapped a fair amount with the slowly tapered group. The taper was the same regardless of the drug's half life, and regardless of whether the patient was on AED polytherapy, a high medication dosage, or had more frequent or severe seizures. Longer half-life drugs and high medication burden may make it harder to provoke seizures or may be riskier if these combinations are seen in patients with very hard to control epilepsy. For example, levetiracetam tapering approached significance between groups (p = 0.08) and may have become significant with a larger study. Using a metric such as total medication burden (i.e., defined daily dose) may help reduce this confound. Also, a more disparate taper (i.e., greater or less than 50% reduction) may allow a way to distinguish the groups without substantially decreasing safety and may be easier to uncover an effect of rate of taper. Additionally, one-third of patients were ineligible to participate in the study due to daily seizures or a history of having had status epilepticus. There were more patients on higher doses of AEDs. In reality, we need to design studies that can address these differences to understand how to adjust tapering if necessary or strictly stick to the protocol as we cannot just eliminate patients from AED withdrawal if they are not meeting criteria in the “real life” EMU. Countering all of these criticisms though is the randomized methodology as well as the finding that centers with formal protocols for AED tapering have been shown to have fewer seizure clusters on LTM (3), a known risk for SE.
Kumar et al. is an important first step toward developing guidelines to inform protocols for efficacy and safety in the EMU. Future studies could focus on enrolling multiple sites to participate in a prospective double-blinded trial allowing for more disparate and varied rates of drug tapering, including a control where no medication change occurs. Subanalyses that compare children and adults, and type and etiology of epilepsy may be important as it is unclear if the results will apply to all groups that are evaluated in the EMU. Children generally have many more seizures during LTM than adults and have higher rates of SE. Other outcomes could also be gathered; for example, hospital bounce back readmissions following EMU discharge. Safety is critical during and after EMU hospitalization where medications have been altered, and powering the next study for safety outcomes would be very wise.