Are brain MRI abnormalities associated with the semiology of functional seizures?

Abstract Purpose To investigate whether radiologically apparent brain magnetic resonance imaging (MRI) abnormalities are associated with the functional seizure (FS) semiology. Methods All patients with a diagnosis of FS at the epilepsy centers at Shiraz University of Medical Sciences, Iran; Aichi Medical University Hospital, Japan; University of Michigan, USA; University of California, Los Angeles, USA; Emory University School of Medicine, USA; and Hospital el Cruce, Argentina, were studied. Results One hundred patients were included; 77 (77%) had motor functional seizures. Lobar location of brain abnormality did not have an association with the semiology (p = .83). There was no significant difference between ictal behaviors in patients with frontal or parietal lesions compared to those with temporal or occipital lesions. Conclusion There were no associations between functional seizure ictal behaviors and locations of the radiologically apparent brain MRI abnormalities. Further studies are needed to evaluate the underpinnings of varying behaviors in FS.


INTRODUCTION
Functional seizures (FS) comprise as much as 10% of patients seen at comprehensive epilepsy centers; they happen in a heterogeneous patient population and their underlying etiology is not fully clear yet (Asadi-Pooya, 2021,;2017;Popkirov et al., 2019). While each This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC. patient's ictal behavior can be unique, clustering analyses have demonstrated key behavioral subtypes including motor functional seizures and akinetic functional seizures (Asadi-Pooya & Farazdaghi, 2022). Abnormal brain magnetic resonance imaging (MRI) in patients with FS have often been dismissed as incidental findings; however, there is increasing evidence that FS are associated with both structural brain Brain Behav. 2023;13:e2882.
Broadly, these neuroimaging abnormalities may reflect changes in the connectivity between limbic and affective areas, frontal executive control, and the motor networks (Foroughi et al., 2020).
The aim of the current study was to investigate whether radiologically apparent brain MRI abnormalities are associated with the functional seizure semiology. Just as different symptomatogenic zones in epileptic seizures produce varying ictal behaviors, we hypothesized that varying neuroimaging abnormalities may be associated with varying ictal behaviors in FS. In specific, we hypothesized that the frontal and parietal lesions are associated with motor semiology while temporal and occipital lesions are associated with nonmotor (akinetic) semiology.

Participants
All patients ( were excluded. Because our hypothesis relied on patterns in brain MRI abnormalities, patients with normal brain MRIs or without such neuroimaging were excluded (we did not keep track of such patients).

Data collection
Age at functional seizure onset, age at diagnosis, sex, seizure semiology (motor functional seizures versus akinetic functional seizures),

Statistical analyses
Values were presented as number (percent) of subjects for categorical variables and as mean ± standard deviation for continuous variables.
The IBM SPSS Statistics (version 25.0) was used for the statistical analyses. Pearson's chi-square test was used. A p value (2-sided) less than .05 was considered as significant.

Standard protocol approvals, registrations, and patient consents
The Institutional Review Boards of all the centers approved this study.

RESULTS
In total, 100 patients were included ( Furthermore, it seems that the types of brain MRI abnormalities seen (

DISCUSSION
In the current study, we did not observe a significant association between functional seizure motor semiology and neuroimaging abnormality location (i.e., lobe or side of the lesion). In one previous study of 206 patients with FS, markers of brain abnormalities (e.g., epileptiform EEG changes, MRI abnormalities, and neuropsychological deficits) were studied to explore whether brain disorders were associated with an increased risk of FS (Reuber et al., 2002). At least one marker of brain disorder was detected in 22% of the patients (MRI changes in 27% of those examined or 9.7% of the whole group, epileptiform potentials in 8.7%, and neuropsychological deficits in 9.7% of the whole group). The authors concluded that brain abnormalities play a role in the development of FS (Reuber et al., 2002). Furthermore, there is increasing evidence that FS are associated with structural and functional brain abnormalities (Asadi-Pooya & Homayoun, 2020;Foroughi et al., 2020;Kerr et al., 2021;McSweeney et al., 2017;Tavakoli Yaraki et al., 2022). Therefore, it may be worthwhile to pursue the hypothesis of "varying neuroimaging abnormalities may be associated with varying ictal behaviors in FS" by using advanced neuroimaging techniques (see below).
In our study, the nature of neuroimaging abnormalities was diverse and there were no clear patterns in the observed abnormalities even within lobar locations. This marked diversity was also observed in the results of studies of radiologically apparent abnormalities and quantitative structural and functional neuroimaging associations with FS (McSweeney et al., 2017). This indicates that there may be other important factors that contribute to ictal behaviors in FS that were not apparent in the radiological analysis of brain MRIs.
During the past two decades, many investigators have tried to study brain abnormalities in patients with FS. These studies have applied various techniques including, functional magnetic resonance imaging (fMRI), EEG, MRI with or without diffusion tensor imaging (DTI), and magnetoencephalography (MEG), among others (Foroughi et al., 2020).
These studies have identified a variety of brain connectivity (functional and structural) abnormalities in patients with FS; the most consistent findings included connectivity abnormalities between brain regions such as sensorimotor cortex, frontal lobes, limbic system, temporoparietal junction, basal ganglia, occipital lobes, and uncinate fasciculus.
However, none of these studies provided a high level of evidence (all of the studies were either cross sectional or retrospective studies with limited sample sizes and most of the studies did not match their cases and their controls with respect to their psychiatric comorbidities) (Foroughi et al., 2020).
It seems that pursuing the concept of brain abnormalities (structural and functional) in patients with FS may result in a breakthrough in identifying the neurobiological underpinnings of FS; however, welldesigned large multicenter studies are needed to investigate this concept.

LIMITATIONS
This study focused on radiologically apparent abnormalities on clinically obtained MRIs. While a significant minority of patients with FS have neuroimaging abnormalities, this still reflects a minority of patients. To address this concern, we combined results from six international Comprehensive Epilepsy Centers to create a relatively large sample size. However, the underlying heterogeneity of abnormalities and factors associated with FS remained broad, indicating that further multisite collaborations are necessary (Perez et al., 2021).
Additionally, we focused on radiologically apparent abnormalities.
Functional neurological disorders (e.g., FS) are defined by the presence of distressing neurological symptoms that are not explained by readily identifiable structural or physiological pathological changes capable of explaining the clinical presentation. Advanced neuroimaging postprocessing techniques and quantitative analysis of MRI morphology may reveal associations that are not appreciated by visual analysis. Finally, we did not have a control group in the current study.

CONCLUSION
There were no clear associations between functional seizure ictal behaviors and locations of the radiologically apparent brain MRI abnormalities. Further studies are needed to evaluate the biological underpinnings of varying ictal behaviors in patients with FS.

AUTHOR CONTRIBUTIONS
Ali A. Asadi-Pooya: study design, data collection, statistical analyses, and manuscript preparation. Others: data collection and manuscript preparation.