Longitudinal analysis of structural connectivity in patients with newly diagnosed focal epilepsy of unknown origin
Introduction
Epilepsy of unknown cause, which, in the past, has been termed “cryptogenic,” accounts for at least one-third of all epilepsy diagnoses.1 In approximately 25 % of patients with focal epilepsy, previously referred to as “partial epilepsy,” no specific cause can be identified using neuroimaging studies and, as such, is classified as focal epilepsy of unknown cause [1].
Mounting evidence has suggested that epilepsy is a network disease, with focal epilepsy also exhibiting widespread alterations in the network beyond the epileptogenic zone [2]. This is in agreement with findings that patients with focal epilepsy exhibit gray matter atrophy beyond the putative epileptogenic focus [3]. Quantitative magnetic resonance imaging (MRI) provides biologically valid imaging markers and high test-retest reliability, thus representing an objective framework from which to investigate disease extension, which is more sensitive in detecting gray matter atrophy than visual analysis. In patients with temporal lobe epilepsy involving hippocampal sclerosis, the most common refractory focal epilepsy in adults, quantitative MRI analysis has revealed extra-temporal volume reduction as well as extra-hippocampal atrophy [3,4]. In addition, many studies have reported significant volume reduction, even in patients with focal epilepsy of unknown cause [[5], [6], [7]].
Despite the traditional hypothesis that “seizures beget seizures,” controversy remains as to whether epilepsy is a progressive disease. In the fields of neuroimaging research, gray matter atrophy could reflect the progression of epilepsy, especially targeted structures involved in the epilepsy network. Several studies have investigated the relationship between the duration of epilepsy and changes in gray matter volume in focal epilepsy. Some research has demonstrated a significant correlation between gray matter volume reduction and duration of epilepsy in several regions [3,4,[8], [9], [10]], whereas other studies did not reveal any such association [[11], [12], [13], [14]]. These discrepancies are most likely due to methodological differences, such as the method of analysis in cross-sectional [3,8,9,11] versus longitudinal follow-up studies [4,10,[12], [13], [14]]. Cross-sectional studies cannot determine whether neuronal damage occurs progressively through repeated seizures. One basic assumption of cross-sectional studies is that the brain volumes of all patients are same at the same age, which may be incorrect. Thus, longitudinal studies with serial MRI scans better enable the quantification of morphological changes over time than cross-sectional investigations. Furthermore, most previous studies have shared the problem of enrolling heterogeneous patient groups, thereby mixing individuals with newly diagnosed and chronic epilepsy [3,4,6,[8], [9], [10], [11]13]. There are differences between newly diagnosed and chronic epilepsy in many respects, such as response to antiepileptic drugs, prognosis, and mortality rate [15,16]. To address these issues, we performed a longitudinal quantitative MRI study involving patients with newly diagnosed focal epilepsy, who had no structural lesions on their brain MRI.
There have been few reports describing changes in the brain network over time. One cross-sectional study observed a progressive increase in connection strength in the hippocampus over time in patients with mesial temporal lobe epilepsy [17]. Another study reported that interhemispheric hippocampal connectivity exhibited a significant negative correlation with the duration of epilepsy [18]. However, to date, neither longitudinal follow-up studies nor research investigating focal epilepsy of unknown origin have been conducted.
The aim of this longitudinal study, therefore, was to clarify whether there significant alterations in structural volumes and connectivity occur over time in patients with focal epilepsy of unknown origin. We only included patients with newly diagnosed focal epilepsy of unknown origin who had normal brain MRI results on visual inspection. We hypothesized that there are significant alterations in structural volumes and connectivity observed over time in this patient population compared to healthy normal controls.
Section snippets
Subjects
This retrospective study was performed at a tertiary hospital with the approval of the authors’ institutional review board. Forty patients with newly diagnosed focal epilepsy of unknown origin, according to the classification of the International League Against Epilepsy [1], were consecutively recruited from a single tertiary hospital. All included patients had the following: focal epilepsy diagnosed by an epileptologist based on clinical history, seizure semiology, and electroencephalography
Demographic characteristics of the study population
The demographic characteristics of the patients with focal epilepsy of unknown origin were summarized in Table 1. The median duration between the initial and second MRI scans was 18.5 months. Of the 40 patients with focal epilepsy, more than one-half had temporal lobe epilepsy (n = 24 [60 %]), 14 (35 %) had frontal lobe epilepsy, and 2 (5%) had occipital lobe epilepsy. Most of the patients with focal epilepsy were drug-responsive at the time of the second MRI (6 patients with drug-resistant
Discussion
The main finding of the present study is that the structural connectivity in patients with newly diagnosed focal epilepsy of unknown origin increases, increased structural integration and segregation of the brain network, over time in the initial stage, which are consistent with other findings of the present study revealing an increased tendency of brainstem and thalamus volumes. However, we could not find any significant differences including structural volume and connectivity in healthy
Conclusion
We find that the structural connectivity in patients with newly diagnosed focal epilepsy of unknown origin increases, increased structural integration and segregation of the brain network, over time in the initial stage, which are consistent with other findings of the present study revealing increased tendency of brainstem and thalamus volumes. These alterations in increased structural connectivity may be related to underlying epileptogenicity in the initial stages of epilepsy.
CRediT authorship contribution statement
Kang Min Park: Writing - original draft. Seongho Park: Writing - review & editing. Dong Ah Lee: Data curation, Formal analysis. Ho-Joon Lee: Software. Sung Eun Kim: Conceptualization.
Declaration of Competing Interest
None.
Acknowledgements
None.
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Cited by (1)
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Kang Min Park and Seongho Park are co-first authors and contributed equally.