Efficacy of Naloxone in Reducing Postictal Central Respiratory Dysfunction in Patients With Epilepsy
Efficacy of Naloxone in Reducing Postictal Central Respiratory Dysfunction in Patients With Epilepsy
Sudden unexpected death in epilepsy (SUDEP) primarily affects young adults with
 drug-resistant epilepsy, with an incidence of about 0.4%/year. The diagnosis of SUDEP
 requires that anamnestic data and post-mortem examination do not reveal a structural or
 toxicological cause for death. Generalized tonic-clonic seizures (GTCS) are the main risk
 factor for SUDEP, which they appear to trigger in most instances. Indeed, experimental and
 clinical data strongly suggest that most SUDEP result from a postictal respiratory
 dysfunction progressing to terminal apnea, later followed by cardiac arrest.

 Postictal apnea could partly derive from a seizure-induced massive release of endogenous
 opioids. Animal studies suggest that such seizure-related release of endogenous opioid
 peptides participate to termination of seizures. In patients with epilepsy, functional
 imaging studies have confirmed that seizures induce release of endogenous opioids. The
 brainstem respiratory centers contain the highest density in opioid receptors, accounting for
 respiratory depression being one of the cardinal symptoms of opioid overdose.

 The investigators hypothesis is that SUDEP partly results from a post-ictal apnea promoted by
 a GTCS-induced massive release of endogenous opioids, and that an opioid antagonist could
 represent an effective preventive treatment of SUDEP. This could be achieved by chronic
 administration of Naltrexone, an opioid antagonist that has been used in a large population
 of patients with chronic alcoholism at high risk of seizures, without showing any
 pro-convulsant effect. This is a crucial feasibility issue since antagonising a mechanism
 thought to participate to seizure termination could theoretically aggravate seizures.

 Before evaluating the efficacy of chronic administration of naltrexone, it is legitimate to
 perform a proof of concept study by testing the acute effect of an equivalent injectable
 treatment (Naloxone) in the immediate aftermath of GTCS recorded inhospital during video-EEG
 monitoring of patients with refractory epilepsy. One third of these patients develop
 postictal respiratory dysfunction and hypoxemia, which should be reduced by the investigators
 intervention if the investigators hypothesis is correct.

 The main objective of the study is to evaluate the efficacy of 0.4 mg intravenous naloxone,
 versus placebo, administered in the immediate aftermath of a GTCS, in reducing the severity
 of the postictal central respiratory dysfunction occurring after the end of the seizure, as
 measured by pulse oximetry.

 About 25% of patients with drug-resistant partial epilepsy who undergo long-term video-EEG
 monitoring develop at least one partial secondary generalized tonic-clonic seizure. However,
 these patients cannot be individualized a priori. Therefore, all adult patients with
 drug-resistant epilepsy who will undergo long-term video-EEG monitoring in one of the
 participating centres, will lack all exclusion criteria, and will give their written informed
 consent to participate to the study if they develop GTCS, will be included in the study. They
 will all benefit from continuous monitoring of pulse oximetry (together with video, EEG, and
 respiration recordings), and will be equipped with a peripheral venous catheter throughout
 the video-EEG. The modalities of the video-EEG monitoring will be consistent with the current
 practices and similar across the 8 centres (apart from the venous catheter which is not
 standard practice).

 In case of occurrence of a generalized tonic-clonic seizure, patients will be randomized
 (1:1) to receive intravenous naloxone (0.4 mg) or placebo. Placebo will be isotonic sodium
 chloride which preparation and packaging will be centralized to ensure its
 indistinguishability from naloxone. Randomization will be centralized and stratified by
 centre. The evolution from a partial seizure to a GTCS being gradual, and the total duration
 of the seizure ranging from 2 to 3 minutes, the injection will be prepared during the course
 of the seizure. Given the assumptions about the role of endogenous opioids release in the
 spontaneous termination of seizures, naloxone will be administrated immediately after the end
 of the GTCS and not before.

 All digital data (video, EEG, respiration, SpO2) will be centralized and evaluated blind to
 other data by the PI of the study who will not be involved in the video-EEG monitoring of the
 included patients. The same automatic and objective analysis of SpO2 data than the one
 already developed in the PHRC REPOMSE will be performed.
Sample size was revised using a log rank test with a two-sided alternative hypothesis. For a
 significance level of 5% (two-tailed), assuming a hazard ratio of 2.414 calculated, i.e based
 on an effect size similar to the effect size of oxygenotherapy in a delay of 60 seconds
 (Rheims et al., 2019), 40 events should be observed to reject the null hypothesis in 80% of
 cases,. A proportion of 89% of patients being expected to recover SpO2 ≥ 90% 120 seconds
 after the end of the seizure and considering a proportion of unusauble records for technical
 reasons of 20%, at least 54 patients should be randomized.

 Assuming that about 10% of patients with drug-resistant partial epilepsy who undergo
 long-term video-EEG monitoring develop at least one partial secondary generalized
 tonic-clonic seizure, a total of 554 patients will be included in the study.
Inclusion Criteria:

 -  For inclusion

 -  Adult patient (≥ 18 years) suffering from drug-resistant partial epilepsy

 -  Patient undergoing long-term video-EEG monitoring in one of the participating centre
 to record and characterize its seizure

 -  Patient who gave its written informed consent to participate to the study For
 randomization

 -  Patient who suffers a secondary generalized tonic-clonic seizure during the long-term
 video-EEG monitoring while being supervised by a nurse or a physician

 Exclusion Criteria:

 -  Age < 18 years

 -  Patient that has already been randomized in this study

 -  Pregnant or breastfeeding women

 -  Hypersensitivity to naloxone

 -  History of severe heart disease (myocardial infarction, heart failure disorder,
 arrhythmia severe hypertension)

 -  Ongoing opioïd treatment, including both pure agonists and partial agonists

 -  Addiction to opioïds, heroin, or any similar substance

 -  Patient participating in another drug trial for less than 2 months