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The Sodium Channel B4-Subunits are Dysregulated in Temporal Lobe Epilepsy Drug-Resistant Patients.

ABSTRACT: Temporal lobe epilepsy (TLE) is the most common type of partial epilepsy referred for surgery due to antiepileptic drug (AED) resistance. A common molecular target for many of these drugs is the voltage-gated sodium channel (VGSC). The VGSC consists of four domains of pore-forming ?-subunits and two auxiliary ?-subunits, several of which have been well studied in epileptic conditions. However, despite the ?4-subunits' role having been reported in some neurological conditions, there is little research investigating its potential significance in epilepsy. Therefore, the purpose of this work was to assess the role of SCN4? in epilepsy by using a combination of molecular and bioinformatics approaches. We first demonstrated that there was a reduction in the relative expression of SCN4B in the drug-resistant TLE patients compared to non-epileptic control specimens, both at the mRNA and protein levels. By analyzing a co-expression network in the neighborhood of SCN4B we then discovered a linkage between the expression of this gene and K+ channels activated by Ca2+, or K+ two-pore domain channels. Our approach also inferred several potential effector functions linked to variation in the expression of SCN4B. These observations support the hypothesis that SCN4B is a key factor in AED-resistant TLE, which could help direct both the drug selection of TLE treatments and the development of future AEDs.

SUBMITTER: Sheilabi MA

PROVIDER: S-EPMC7216270 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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The Sodium Channel B4-Subunits are Dysregulated in Temporal Lobe Epilepsy Drug-Resistant Patients.

Sheilabi Mariam A MA Takeshita Louise Y LY Sims Edward J EJ Falciani Francesco F Princivalle Alessandra P AP

International journal of molecular sciences 20200422 8

Temporal lobe epilepsy (TLE) is the most common type of partial epilepsy referred for surgery due to antiepileptic drug (AED) resistance. A common molecular target for many of these drugs is the voltage-gated sodium channel (VGSC). The VGSC consists of four domains of pore-forming α-subunits and two auxiliary β-subunits, several of which have been well studied in epileptic conditions. However, despite the β4-subunits' role having been reported in some neurological conditions, there is little res ...[more]

PMID: 32331418

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Project description:Despite reported success, surgery for pharmacoresistant seizures is often seen as a last resort. Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death.We sought to determine whether surgery soon after failure of 2 antiepileptic drug (AED) trials is superior to continued medical management in controlling seizures and improving quality of life (QOL).The Early Randomized Surgical Epilepsy Trial (ERSET) is a multicenter, controlled, parallel-group clinical trial performed at 16 US epilepsy surgery centers. The 38 participants (18 men and 20 women; aged ?12 years) had mesial temporal lobe epilepsy (MTLE) and disabling seizues for no more than 2 consecutive years following adequate trials of 2 brand-name AEDs. Eligibility for anteromesial temporal resection (AMTR) was based on a standardized presurgical evaluation protocol. Participants were randomized to continued AED treatment or AMTR 2003-2007, and observed for 2 years. Planned enrollment was 200, but the trial was halted prematurely due to slow accrual.Receipt of continued AED treatment (n = 23) or a standardized AMTR plus AED treatment (n = 15). In the medical group, 7 participants underwent AMTR prior to the end of follow-up and 1 participant in the surgical group never received surgery.The primary outcome variable was freedom from disabling seizures during year 2 of follow-up. Secondary outcome variables were health-related QOL (measured primarily by the 2-year change in the Quality of Life in Epilepsy 89 [QOLIE-89] overall T-score), cognitive function, and social adaptation.Zero of 23 participants in the medical group and 11 of 15 in the surgical group were seizure free during year 2 of follow-up (odds ratio = ?; 95% CI, 11.8 to ?; P < .001). In an intention-to-treat analysis, the mean improvement in QOLIE-89 overall T-score was higher in the surgical group than in the medical group but this difference was not statistically significant (12.6 vs 4.0 points; treatment effect = 8.5; 95% CI, -1.0 to 18.1; P = .08). When data obtained after surgery from participants in the medical group were excluded, the effect of surgery on QOL was significant (12.8 vs 2.8 points; treatment effect = 9.9; 95% CI, 2.2 to 17.7; P = .01). Memory decline (assessed using the Rey Auditory Verbal Learning Test) occurred in 4 participants (36%) after surgery, consistent with rates seen in the literature; but the sample was too small to permit definitive conclusions about treatment group differences in cognitive outcomes. Adverse events included a transient neurologic deficit attributed to a magnetic resonance imaging-identified postoperative stroke in a participant who had surgery and 3 cases of status epilepticus in the medical group.Among patients with newly intractable disabling MTLE, resective surgery plus AED treatment resulted in a lower probability of seizures during year 2 of follow-up than continued AED treatment alone. Given the premature termination of the trial, the results should be interpreted with appropriate caution.clinicaltrials.gov Identifier: NCT00040326.

Project description:BackgroundCurrently, more than one-third of patients with drug-resistant temporal lobe epilepsy (TLE) continue to develop seizures after resection surgery. Dynamic functional network connectivity (DFNC) analyses, capturing temporal properties of functional connectivity during MRI acquisition, may help us identify unfavorable surgical outcomes. The purpose of this work was to explore the association of DFNC variations of preoperative resting-state MRI and surgical outcomes in patients with drug-resistant TLE.MethodsWe evaluated 61 patients with TLE matched for age and gender with 51 healthy controls (HC). Patients with TLE were classified as seizure-free (n = 39) and not seizure-free (n = 16) based on the Engel surgical outcome scale. Six patients were unable to confirm the postoperative status and were not included in the subgroup analysis. The DFNC was calculated using group spatial independent component analysis and the sliding window approach.ResultsDynamic functional network connectivity analyses suggested two distinct connectivity "States." The dynamic connectivity state of patients with TLE was different from HC. TLE subgroup analyses showed not seizure-free (NSF) patients spent significantly more time in State II compared to seizure-free (SF) patients and HC. Further, the number of transitions from State II to State I was significantly lower in NSF patients. SF patients had compensatory enhancement of DFNC strengths between default and dorsal attention network, as well as within the default network. While reduced DFNC strengths of within-network and inter-network were both observed in NSF patients, patients with abnormally temporal properties and more extension DFNC strength alterations were less likely to receive seizure freedom.ConclusionsOur study indicates that DFNC could offer a better understanding of dynamic neural impairment mechanisms of drug-resistant TLE functional network, epileptic brain network reorganization, and provide an additional preoperative evaluation support for surgical treatment of drug-resistant TLE.

Dataset Information

The Sodium Channel B4-Subunits are Dysregulated in Temporal Lobe Epilepsy Drug-Resistant Patients.

Publications

The Sodium Channel B4-Subunits are Dysregulated in Temporal Lobe Epilepsy Drug-Resistant Patients.

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