Provocative induction of psychogenic nonepileptic seizures: Noninferiority of an induction technique without versus with placebo

Abstract

Summary We aim to demonstrate, in a sufficiently powered and standardized study, that the success rate of inducing psychogenic nonepileptic seizures (PNES) without placebo (saline infusion) is noninferior to induction with placebo. The clinical data of 170 consecutive patients with suspected PNES who underwent induction with placebo from January 21, 2009 to March 31, 2013 were pair‐matched with 170 consecutive patients with suspected PNES who underwent the same induction technique but without addition of placebo from April 1, 2013 to February 7, 2018 at the same center. The success rates of induction were 79.4% (135/170) without placebo and 73.5% (125/170) with placebo. The difference of these two proportions was 5.9%, with two‐sided 95% confidence interval ranging from −3.6% to 15.2%, indicating a non–statistically significant difference. The lower bound of the 95% confidence interval (−3.6%) was above the noninferiority margin (δ = −5%), hence inferring noninferiority of induction without versus with placebo. The greater cumulative induction experiences of the clinician performer (influencing the manner/presentation of induction) may supplant the potential advantage from addition of placebo (the means utilized). Among experienced performers, provocative induction without placebo should be the preferred diagnostic approach, given more ethically acceptable transparency and the noninferior success rate when compared to the same induction technique with placebo.

Suggestive seizure induction for inpatients with suspected psychogenic nonepileptic seizures

“…In line with previous findings from our group, 9 most patients who experienced a seizure during suggestive induction did so through hyperventilation or photic stimulation, but 44% only did so after an intravenous injection (accounting for 25% of all placebo inductions performed across the study). Although some have argued for the abolishment of intravenous placebo for suggestive induction in favor of exclusively non‐invasive, placebo procedures (hyperventilation or photic stimulation), 10,11 our findings suggest that this will come at a significant cost to the diagnostic yield. Indeed, although Gogia et al 11 reported a high diagnostic yield of 47% for non‐invasive suggestion techniques among 169 patients with PNES, their initial study population also included 168 patients (40% of total) who remained without a diagnosis.…”

“…Indeed, although Gogia et al 11 reported a high diagnostic yield of 47% for non‐invasive suggestion techniques among 169 patients with PNES, their initial study population also included 168 patients (40% of total) who remained without a diagnosis. However, in a large study that retrospectively compared two pair‐matched cohorts of 170 patients each who underwent suggestive induction with or without saline injection, Chen et al 10 showed there was no statistically significant difference in the induction rate between protocols. Our current study was not designed to re‐examine this finding.…”

“…7,8 Suggestive induction has been used in epileptology for many decades, with newer protocols minimizing deception and favoring noninvasive suggestion techniques. 9,10 However, there is currently no single standard of care regarding seizure induction, and practices vary widely internationally.…”

“…This is usually achieved through long‐term video‐EEG monitoring over several days in specialized epilepsy units, 6 or through suggestive seizure induction during video‐EEG recording 7,8 . Suggestive induction has been used in epileptology for many decades, with newer protocols minimizing deception and favoring noninvasive suggestion techniques 9,10 . However, there is currently no single standard of care regarding seizure induction, and practices vary widely internationally.…”

Use of suggestive seizure manipulation methods in the investigation of patients with possible psychogenic nonepileptic seizures—An international ILAE survey

“…These concerns related more to the ethics of nocebo induction than potential harms, with many respondents agreeing that provocative techniques may either be ethically problematic (unfortunately the survey design of our research prevented interrogating this further) or might harm the doctor‐patient relationship. There is some evidence that SSM protocols without invasive techniques such as IV nocebo are noninferior to invasive ones (ie, statistically as likely to be diagnostically helpful) 27 . However, since several conventional noninvasive techniques may also reduce the threshold for epileptic seizures (especially hyperventilation and photic stimulation), there may remain contexts where the risks of an epileptic seizure are felt sufficiently high to make alternative methods of nocebo induction preferable (one such context which has been cited is the late stage of pregnancy) 32 .…”