Perampanel in achieving status epilepticus cessation: A systematic review

Highlights

• Status epilepticus necessitates rapid seizure control.

• Perampanel has been shown to work in lithium-pilocarpine models.

• Perampanel was given at 2–32 mg between 30 min and 51 days from status epilepticus onset.

• Status epilepticus cessation ranged from 2 h to 51 days after perampanel initiation.

• Perampanel may be a possible therapeutic option, but requires further clinical studies.

Abstract

Background

Status epilepticus (SE) is a neurological emergency necessitating rapid seizure control to prevent long-term consequences. Perampanel (PER) is a novel selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor antagonist that demonstrated efficacy and safety in lithium-pilocarpine models of SE; however, data in humans are limited. This systematic review was performed to assess the efficacy and safety of PER in patients with SE, RSE, and SRSE.

Methods

We searched MEDLINE (accessed through PubMed), Embase, Scopus, Cochrane Library, and ClinicalTrials.gov from inception until May 30, 2021 to identify all human studies on PER for the treatment of SE of any type and etiology. An additional search was performed on DANS Easy Archive, in which OpenGrey data were stored, from inception until January 10, 2022 and conference proceedings by the International League Against Epilepsy from 2011 onward. The GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach was used to assess the overall certainty of the body of evidence.

Results

Twenty-one studies (7 case reports, 9 case series, and 5 retrospective cohort studies) were included with a total of 369 cases of SE in 368 patients aged 11 months to 99 years, of which 56.2% were female. Seizures of the majority were refractory (n = 220), super refractory SE (n = 70), or either (n = 81) with prominent motor symptoms (n = 284) and are associated with a structural etiology (n = 218). The number of antiseizure medications and/or anesthetics used prior to PER ranged from 1 to 13. PER was administered in 324 cases and was initiated at a dose of 2–36 mg between 30 min to 59 days from SE onset. SE cessation ranged from 1 h to 4 weeks from PER initiation. A total of 119 cases (36.6%) were considered PER responders. According to the GRADE approach, there is very low certainty of evidence for all outcomes.

Conclusions

The real-world data of PER as a possible therapeutic option in SE of any type are increasing. However, there is very low certainty of evidence for its use and this requires further clinical studies to establish the appropriate timing, dosing, and titration that are efficacious and safe for SE cessation.

Introduction

Status epilepticus (SE) is a neurological emergency defined as a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms that lead to abnormally prolonged seizures (>5 min for tonic-clonic SE, >10 min for focal SE, and >15 min for absence SE) [1]. This devastating condition can cause long-term consequences, including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures [1]. Data from the United States (US) National Hospital Discharge Survey from 1979 to 2010 showed an increase in incidence of SE from 3.5 to 12.5 per 100,000 and a cumulative in-hospital mortality rate of 9.2% without significant change over the study period [2].

Treatment of SE should target rapid seizure control (emergent-control phase) and prevention of further seizures (urgent-control phase) with the use of intravenous (IV) benzodiazepines and IV antiseizure medications (ASMs), respectively [3]. Those who do not respond to at least two appropriately selected and dosed parenteral medications, including benzodiazepines, are considered to have refractory SE (RSE) [2], [4]. Super-refractory SE (SRSE) is defined as SE that continues for 24 h or more after the onset of anesthetic therapy, including those in whom SE recurs while on appropriate anesthetic treatment or after withdrawal requiring reintroduction of anesthetic treatment [4]. Progression to RSE is seen in approximately 12–43% and to SRSE in 10–15% in patients with SE [2], [5].

Research in animal models has described several mechanisms that contribute to the development of SE including loss of inhibitory γ-aminobutiric acid (GABA)_A neuronal activity due to the internalization of postsynaptic receptors and sustained glumatate-mediated excitatory activity due to an increase in N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic (AMPA) receptors. The alteration in GABA_A receptors might explain the resistance of SE to benzodiazepines leading to RSE and SRSE [6]. Perampanel (PER), a novel selective, noncompetitive AMPA receptor antagonist, may be effective in this condition. It has been approved by the US Food and Drug Administration (USFDA) as treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy ≥ 4 years and as adjunct treatment of primary generalized tonic-clonic seizures in patients aged ≥ 12 years [7]. However, clinical use of PER in SE has only been studied in animal models and remains limited to case reports and case series in humans [8]. This systematic review aimed to assess the efficacy and safety of PER in patients with SE, RSE, and SRSE.