Psychiatry Research 285 (2020) 112812

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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Review article

International multicenter studies on psychogenic nonepileptic seizures: T

A systematic review
Ali A. Asadi-Pooyaa,b
a
Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
b
Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, PA, USA

ARTICLE INFO ABSTRACT

Keywords: The aim of the current paper is to systematically review the literature on the existing international multicenter
Psychogenic studies on various aspects of PNES and to highlight their findings and significance. I searched the electronic
Seizure database PubMed for articles that included any of these search terms: Non-epileptic seizures, Nonepileptic
International seizures, Pseudoseizures, Non-epileptic events, Nonepileptic events, Dissociative seizures, Psychogenic, PNES,
Multicenter
AND “international” or “multicenter” or “cross cultural”, in their abstracts and titles and published before
Review
August 6, 2019. I searched PsycINFO database (keywords in the abstracts) and also included some of the re-
ferences of the selected articles if they were relevant. I could identify 12 related manuscripts through the search
strategy. These included seven studies on patients with PNES, two surveys, and three consensus group reports.
This systematic review showed that international and cross-cultural studies on PNES to date are very limited in
number and quality. However, these limited studies have resulted in intriguing observations and conclusions.
International and cross-cultural studies may make important contributions to our understanding of different
aspects of PNES across borders.

1. Introduction
Psychogenic nonepileptic seizures (PNES) represent a universal
human condition and are recognized as a worldwide phenomenon
(Hingray et al., 2018). They are characterized by self-limited events
that semiologically may resemble epileptic seizures, but without ictal
epileptiform discharges; they are associated with psychological pro-
blems (Asadi-Pooya and Sperling, 2015). It is believed that despite
cultural and socioeconomic differences, patients with PNES from dif-
ferent countries share several similarities (Asadi-Pooya et al., 2019a).
Nevertheless, patients with PNES are a heterogeneous patient popula-
tion that may differ in their life experiences and psychiatric co-
morbidities (Asadi-Pooya and Sperling, 2015). Hence, it is reasonable to
assume that there might be some differences between patients from
different cultures and various populations. Two previous studies in-
vestigated clinical variables in a large international sample of patients
with adult-onset PNES (Asadi-Pooya et al., 2019b) and pediatric-onset
PNES (Asadi-Pooya et al., 2019c); both of these multicenter interna-
tional studies showed that there were significant semiological differ-
ences between the countries (Asadi-Pooya et al., 2019b,c). Therefore, it
seems that international and cross-cultural studies may make important
contributions to our understanding of PNES across borders and among
different cultures.
The aim of the current paper is to systematically review the litera-
ture on the existing international multicenter studies on various aspects
of PNES and to highlight their findings and significance.
2. Materials and methods
In order to retrieve all the relevant scientific literature on the topic, I
searched the electronic database MEDLINE (accessed through PubMed)
for articles that included any of these search terms: Non-epileptic sei-
zures, Nonepileptic seizures, Pseudoseizures, Non-epileptic events,
Nonepileptic events, Dissociative seizures, Psychogenic, PNES, AND
“international” or “multicenter” or “cross cultural”, in their abstracts
and titles and published before August 6, 2019. Articles not written in
English and review articles were excluded. I selected the relevant ar-
ticles by first screening their titles and abstracts, and subsequently
reading in full any articles that appeared to potentially contain relevant
information. I searched PsycINFO database (keywords in the abstracts)
and also included some of the references of the selected articles if they
were relevant. Duplicate articles were excluded. The quality of the
evidence was rated following the American Academy of Neurology's
guidelines (Table 1) (Gronseth et al., 2017). Reporting was according to
the PRISMA (preferred reporting items for systematic reviews and
meta-analyses) statement (Fig. 1) (Moher et al., 2009).

E-mail address: aliasadipooya@yahoo.com.

https://doi.org/10.1016/j.psychres.2020.112812
Received 24 November 2019; Received in revised form 21 January 2020; Accepted 25 January 2020
Available online 25 January 2020
0165-1781/ © 2020 Elsevier B.V. All rights reserved.
A.A. Asadi-Pooya Psychiatry Research 285 (2020) 112812

Table 1 However, these limited studies have resulted in intriguing observations

Classification of evidence. and conclusions. More than a handful of recent international studies on
Classification Criteria patients with PNES have shown that there are significant semiological
differences between countries and cultures, both in adult and pediatric
I Prospective cohort study with all relevant confounders controlled populations (Ho et al., 2019; Asadi-Pooya et al., 2019a,b,c; Asadi-
or masked or objective outcome assessments, and
Pooya et al., 2017). This implies that the population background de-
a) < 3 primary outcomes
b) clearly defined inclusion and exclusion criteria
termined by cultural, ethnic, and religious differences may influence
c) ≥ 80% study completion rate the semiology of PNES (Asadi-Pooya et al., 2019b). In addition, there
II Retrospective cohort study or case-control study meeting all other are subtle semiological differences between men and women with PNES
class I criteria (Asadi-Pooya.et al., 2019d). While social, psychological, and genetic
III Cohort study or case-control study meeting all class I or II criteria
factors may interact with lifetime adverse experiences (e.g., sexual
except a, b, or c (above)
IV Studies not meeting the above criteria abuse) in the inception of PNES (Asadi-Pooya and Bahrami, 2019) the
link is not yet clear and this is an interesting avenue for future studies.
Adapted from reference (Gronseth et al., 2017). Another international study on patients suggested that the etiology of
PNES might be different in patients with PNES-only compared with that
3. Results in those with comorbid PNES and epilepsy (Wissel et al., 2016). It has
been speculated that epilepsy may contribute to the risk of developing
I could identify 12 related manuscripts through the search strategy. PNES not only through biologic mechanisms, but also due to the ex-
These included seven studies on patients with PNES, two surveys, and perience of epileptic seizures that may provide an opportunity for
three consensus group reports. Tables 2–4, and Fig. 1 describe the de- model learning (Reuber 2009).
tails of the search process and its results. Table 5 summarizes the in- The remaining international studies did not investigate patients
cluded studies and their quality ratings. with PNES; two were surveys (LaFrance et al., 2012; Hingray et al.,
2018) and three were consensus group reports (LaFrance et al., 2013;
Kanemoto et al., 2017; Gasparini et al., 2019). One survey showed that
4. Discussion PNES are a health problem around the world and health care for PNES
could be improved (Hingray et al., 2018). Another survey demonstrated
This systematic review showed that international and cross-cultural that there are some differences in PNES evaluation and management
studies on PNES to date are very limited in number and quality.

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram of the study.

2
A.A. Asadi-Pooya Psychiatry Research 285 (2020) 112812

Table 2
The search keywords included “international” and those in the first column of the table.
Medline (PubMed) (Title/Abstract) PsycINFO (Abstract)
Keywords (AND “international”) Primary hints Relevant articles Primary hints Relevant articles

Non-epileptic seizures 12 1 8 0
Nonepileptic seizures 36 7 18 3 (3 duplicates)
Pseudoseizures 7 0 2 0
Non-epileptic events 6 0 5 0
Nonepileptic events 9 0 4 0
Dissociative seizures 2 0 2 0
Psychogenic 177 9 (8 duplicates) 101 3 (3 duplicates)
PNES 24 9 (9 duplicates) 1 0
Total 273 26 (17 duplicates) 141 6 (6 duplicates)

Table 3
The search keywords included “multicenter” and those in the first column of the table.
Medline (PubMed) (Title/Abstract) PsycINFO (Abstract)
Keywords (AND “multicenter”) Primary hints Relevant articles Primary hints Relevant articles

Non-epileptic seizures 3 0 1 0
Nonepileptic seizures 16 5 (4 duplicates) 4 1 (duplicate)
Pseudoseizures 0 0 0 0
Non-epileptic events 0 0 0 0
Nonepileptic events 2 1 (duplicate) 0 0
Dissociative seizures 0 0 0 0
Psychogenic 33 5 (5 duplicates) 6 1 (duplicate)
PNES 14 5 (5 duplicates) 4 1 (duplicate)
Total 66 16 (15 duplicates) 15 3 (3 duplicates)

Table 4
The search keywords included “cross cultural” and those in the first column of the table.
Medline (PubMed) (Title/Abstract) PsycINFO (Abstract)
Keywords (AND “cross cultural”) Primary hints Relevant articles Primary hints Relevant articles

Non-epileptic seizures 1 0 0 0
Nonepileptic seizures 13 2 (1 duplicate) 8 2 (2 duplicates)
Pseudoseizures 0 0 0 0
Non-epileptic events 0 0 0 0
Nonepileptic events 0 0 0 0
Dissociative seizures 0 0 1 0
Psychogenic 22 2 (2 duplicates) 18 2 (2 duplicates)
PNES 14 2 (2 duplicates) 8 2 (2 duplicates)
Total 50 6 (5 duplicates) 35 6 (6 duplicates)

between clinicians in the USA and in Chile (LaFrance et al., 2012),
which were probably the result of the existing differences in the access
to resources between the two countries. Interestingly, one of the studies
that investigated patients internationally showed that delay in diag-
nosis of PNES may represent a major issue, especially in resource-lim-
ited countries (9.9 years in Brazil vs. 5.6 years in the USA; P = 0.001)
(Asadi-Pooya et al., 2019d). These three international studies
(LaFrance et al., 2012; Hingray et al., 2018; Asadi-Pooya et al., 2019d)
corroborate the notion that delay in making a definite diagnosis of
PNES is a significant issue even in the developed world, but the issue is
much worse in the developing countries with limited access to re-
sources.
The international consensus group reports have also provided in-
teresting and important materials (LaFrance et al., 2013; Kanemoto
et al., 2017; Gasparini et al., 2019). While these reports are not in line
with the primary aim of the current study, it is worthwhile to sum-
marize them for the sake of completeness. First, to make a correct di-
agnosis of PNES different combinations of data including, patient his-
tory, witness reports, clinician observations, and video-EEG monitoring
and ictal recordings are necessary (LaFrance et al., 2013; Asadi-
Pooya et al., 2017). In order to make a documented diagnosis, history
should be compatible with the diagnosis of PNES; events should be
witnessed by a clinician experienced in making the diagnosis of par-
oxysmal events, showing semiology typical of PNES while on video-EEG
monitoring; and finally, no epileptiform activity should be detected
immediately before, during or after the attack that was captured on
ictal video-EEG recording (LaFrance et al., 2013). However, the existing
significant limitation in access to resources may hamper making a
documented or even a clinically established diagnosis of PNES in many
places in the world; this highlights the need for developing practical
algorithms and formulas for the diagnosis of PNES. These algorithms
should be easily applicable and practical and less dependent on re-
sources (e.g., human resources such as epileptologists or equipment
such as video-EEG monitoring units), while maintaining reliability
(with acceptable sensitivity and specificity rates). Finally, one of the
consensus group reports highlighted that PNES management should be
multidisciplinary (Gasparini et al., 2019); but, again strategies should
be developed to make this multidisciplinary management process less
dependent on sophisticated or expensive resources to make it available
and possible globally and for all.
In conclusion, this systematic review showed that international and
cross-cultural studies on PNES are scarce. However, these limited

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A.A. Asadi-Pooya Psychiatry Research 285 (2020) 112812

Table 5
Details of the international multicenter manuscripts in patients with psychogenic nonepileptic seizures (PNES).
1st author/ Year Study title and design Main results Class of
evidence

Wissel/ 2016 Which patients with epilepsy are at risk for PNES? A multicenter Right-hemispheric electrographic seizures may be more common III
case-control study among patients with epilepsy who develop comorbid PNES
Kanemoto/ 2017 PNES around the world: Where we are now and how we can close This paper describes gaps in care of patients with PNES (not only in less IV
the diagnosis and treatment gaps-an ILAE PNES Task Force developed countries)
report/ an international workshop report
Hingray/ 2017 Access to diagnostic and therapeutic facilities for PNES: An This survey demonstrated that PNES are a health problem around the IV
international survey by the ILAE PNES Task Force world. Health care for PNES could be improved
Gasparini/ 2019 Management of PNES: a multidisciplinary approach/ An Approach to PNES diagnosis should comply with the ILAE IV
international consensus group report recommendations. PNES management should be multidisciplinary.
High-quality long-term studies are needed to standardize PNES
management
LaFrance Jr/ 2012 Comparing standard medical care for nonepileptic seizures in There are some differences in PNES evaluation and management IV
Chile and the United States/ survey of clinicians between neurologists and other clinicians in the US and in Chile
LaFrance Jr / Minimum requirements for the diagnosis of PNES: A staged Levels of diagnostic certainty were developed including possible, IV
2013 approach/ An international consensus group report probable, clinically established, and documented diagnosis, based on
the availability of history, witnessed event, and investigations,
including video-EEG recording
Asadi-Pooya/ Semiology of PNES: A retrospective multicenter international Some characteristics of PNES were different between the two groups III
2017 study (USA vs. Brazil). Delay in diagnosis of PNES may represent a major
issue in resource-limited countries
Asadi-Pooya/ PNES in children and adolescents: Young patients with PNES across borders share more similarities than III
2019a A retrospective multicenter international study differences with regard to their demographic and clinical
characteristics
Asadi-Pooya/ Adult-onset PNES: A retrospective multicenter international study There were significant semiological differences among the countries III
2019b
Asadi-Pooya/ Pediatric-onset PNES: A retrospective multicenter international Patients with pediatric-onset PNES from different countries were III
2019c study similar on many risk factors associated with PNES. However, intriguing
differences were also noted with regard to seizure semiology, which
might be the result of cultural factors
Asadi-Pooya/ Sex differences in demographic and clinical characteristics of Similarities between females and males outweigh the differences. III
2019d PNES: A retrospective multicenter international study However, notable differences are that females more often report
lifetime adverse experiences and auras
Ho/2019 Psychogenic nonepileptic seizures in Hawaii's Ethno-racially There were significant differences in the expression of PNES across key III
diverse population ethno-racial groups for the Islands of Hawaii

studies have resulted in intriguing observations and conclusions.
International and cross-cultural studies may make important contribu-
tions to our understanding of different aspects of PNES across borders
and between cultures.
Declaration of Competing Interest
Honoraria from Cobel Daruo, Sanofi, and RaymandRad; Royalty:
Oxford University Press (Book publication).
Acknowledgments
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.psychres.2020.112812.
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