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CpG methylation signature defines human temporal lobe epilepsy and predicts drug-resistant.

ABSTRACT: AIMS:Temporal lobe epilepsy (TLE) is the most common focal epilepsy syndrome in adults and frequently develops drug resistance. Studies have investigated the value of peripheral DNA methylation signature as molecular biomarker for diagnosis or prognosis. We aimed to explore methylation biomarkers for TLE diagnosis and pharmacoresistance prediction. METHODS:We initially conducted genome-wide DNA methylation profiling in TLE patients, and then selected candidate CpGs in training cohort and validated in another independent cohort by employing machine learning algorithms. Furthermore, nomogram comprising DNA methylation and clinicopathological data was generated to predict the drug response in the entire patient cohort. Lastly, bioinformatics analysis for CpG-associated genes was performed using Ingenuity Pathway Analysis. RESULTS:After screening and validation, eight CpGs were identified for diagnostic biomarker with an area under the curve (AUC) of 0.81 and six CpGs for drug-resistant prediction biomarker with an AUC of 0.79. The nomogram for drug-resistant prediction comprised methylation risk score, disease course, seizure frequency, and hippocampal sclerosis, with AUC as high as 0.96. Bioinformatics analysis indicated drug response-related CpGs corresponding genes closely related to DNA methylation. CONCLUSIONS:This study demonstrates the ability to use peripheral DNA methylation signature as molecular biomarker for epilepsy diagnosis and drug-resistant prediction.

SUBMITTER: Xiao W

PROVIDER: S-EPMC7539843 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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CpG methylation signature defines human temporal lobe epilepsy and predicts drug-resistant.

Xiao Wenbiao W Liu Chaorong C Zhong Kuo K Ning Shangwei S Hou Rui R Deng Na N Xu Yuchen Y Luo Zhaohui Z Fu Yujiao Y Zeng Yi Y Xiao Bo B Long Hongyu H Long Lili L

CNS neuroscience & therapeutics 20200610 10

<h4>Aims</h4>Temporal lobe epilepsy (TLE) is the most common focal epilepsy syndrome in adults and frequently develops drug resistance. Studies have investigated the value of peripheral DNA methylation signature as molecular biomarker for diagnosis or prognosis. We aimed to explore methylation biomarkers for TLE diagnosis and pharmacoresistance prediction.<h4>Methods</h4>We initially conducted genome-wide DNA methylation profiling in TLE patients, and then selected candidate CpGs in training coh ...[more]

PMID: 32519815

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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.

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CpG methylation signature defines human temporal lobe epilepsy and predicts drug-resistant.

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CpG methylation signature defines human temporal lobe epilepsy and predicts drug-resistant.

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