Dysfunctional Brain Networking among Autonomic Regulatory Structures in Temporal Lobe Epilepsy Patients at High Risk of Sudden Unexpected Death in Epilepsy

Abstract

BackgroundSudden unexpected death in epilepsy (SUDEP) is common among young people with epilepsy. Individuals who are at high risk of SUDEP exhibit regional brain structural and functional connectivity (FC) alterations compared with low-risk patients. However, less is known about network-based FC differences among critical cortical and subcortical autonomic regulatory brain structures in temporal lobe epilepsy (TLE) patients at high risk of SUDEP.Methods32 TLE patients were risk-stratified according to the following clinical criteria: age of epilepsy onset, duration of epilepsy, frequency of generalized tonic–clonic seizures, and presence of nocturnal seizures, resulting in 14 high-risk and 18 low-risk cases. Resting-state functional magnetic resonance imaging (rs-fMRI) signal time courses were extracted from 11 bilateral cortical and subcortical brain regions involved in autonomic and other regulatory processes. After computing all pairwise correlations, FC matrices were analyzed using the network-based statistic. FC strength among the 11 brain regions was compared between the high- and low-risk patients. Increases and decreases in FC were sought, using high-risk > low-risk and low-risk > high-risk contrasts (with covariates age, gender, lateralization of epilepsy, and presence of hippocampal sclerosis).ResultsHigh-risk TLE patients showed a subnetwork with significantly reduced FC (t = 2.5, p = 0.029) involving the thalamus, brain stem, anterior cingulate, putamen and amygdala, and a second subnetwork with significantly elevated FC (t = 2.1, p = 0.031), which extended to medial/orbital frontal cortex, insula, hippocampus, amygdala, subcallosal cortex, brain stem, thalamus, caudate, and putamen.ConclusionTLE patients at high risk of SUDEP showed widespread FC differences between key autonomic regulatory brain regions compared to those at low risk. The altered FC revealed here may help to shed light on the functional correlates of autonomic disturbances in epilepsy and mechanisms involved in SUDEP. Furthermore, these findings represent possible objective biomarkers which could help to identify high-risk patients and enhance SUDEP risk stratification via the use of non-invasive neuroimaging, which would require validation in larger cohorts, with extension to patients with other epilepsies and subjects who succumb to SUDEP.

Sudden unexpected death in epilepsy: The neuro-cardio-respiratory connection

“…A study employing neuroimaging in temporal lobe epilepsy patients showed differences between patients at high and low risk for SUDEP in functional connectivity of brain structures associated with autonomic respiratory and cardiac regulation [12]. A subnetwork of reduced functional connectivity was shown in several areas previously linked to increased SUDEP risk [27], including the thalamus, brain stem, anterior cingulate cortex, putamen and amygdala.…”

“…Attention has been focused on respiratory and CV dysfunction as potential mechanisms of SUDEP [11]. Alterations in brain structure, function, and connectivity have been shown in subjects with epilepsy at risk for SUDEP [12]. Disruption of the central autonomic control could play a major role in SUDEP [13].…”

“…Obtaining insight into its pathophysiologic mechanisms is a cardinal step towards preventing and reducing the incidence of SUDEP. It has been suggested that neuronal networks producing generalized tonicclonic seizures suppress brainstem respiratory or autonomic control centers, leading to hypoventilation, apnea and cardiovascular (CV) collapse [11][12][13]. Furthermore, normal arousal mechanisms appear compromised in these patients.…”

Sodium valproate protects against neuronal ferroptosis in epilepsy via suppressing lysyl oxidase

“…Several syndromes including cognitive decline and depression, usually occur in the epileptogenesis [4,5] , which have a detrimental effect on the life quality of patients. The prevalence of major depression in the general population is 4.9%~7% while the prevalence of depression in patients with epilepsy is as high as 11%-60% [6] . The treatments for epilepsy involve medical treatment, surgical treatment, diet therapy and hormonal interventions, among of which medical treatment is offered as the primary treatment [6,7] .…”

“…The prevalence of major depression in the general population is 4.9%~7% while the prevalence of depression in patients with epilepsy is as high as 11%-60% [6] . The treatments for epilepsy involve medical treatment, surgical treatment, diet therapy and hormonal interventions, among of which medical treatment is offered as the primary treatment [6,7] . Valproic acid (VPA), a traditional broad-spectrum antiepileptic drug, is known to have diverse pharmacological effects, such as prolongation of sodium-channel inactivation [8] , elevation of GABA content in the brain [9] , inhibition of HDAC activity [10] , reduction of reactive oxygen species (ROS) production [11] .…”