Genetic and molecular features of seizure-freedom following surgical resections for focal epilepsy: A pilot study

Louis, Shreya; Busch, Robyn M.; Lal, Dennis; Hockings, Jennifer; Hogue, Olivia; Morita-Sherman, Márcia; Vegh, Deborah; Najm, Imad; Ghosh, Chaitali; Bazeley, Peter; Eng, Charis; Jehi, Lara; Rotroff, Daniel M.

doi:10.3389/fneur.2022.942643

Cited by 4 publications

(5 citation statements)

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“…Tissue samples were collected during surgical resection and subsequently flash frozen as previously described. 12 Total RNA (+miRNA) were extracted using a modified version of the miRNeasy Mini Kit from Qiagen. Tissues were homogenized in QIAzol Lysis Reagent using 5 mm stainless steel beads for 2 min at 20 Hz with a TissueLyser II (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, the value of genetic testing in conjunction with clinical variables for surgical candidacy has proven advantageous, and genomic single nucleotide polymorphisms have shown associations with surgical outcomes. 11 , 12 …”

Section: Introductionmentioning

confidence: 99%

“…In addition to DNA variants, mRNA transcripts and miRNAs have been assessed for association with post-surgical seizure freedom. 12 , 13 When comparing brain transcriptomes from two individuals with late recurring seizures to transcriptomes from four individuals who remained seizure free post-resection, 29 target transcripts were identified. 13 A second study, analysing mRNA and miRNA from brain tissue of 132 and 135 individuals, respectively, did not identify any individual miRNAs or mRNAs associated with surgical outcomes; however, several signalling and metabolic pathways associated with seizure recurrence were significantly enriched.…”

Section: Introductionmentioning

confidence: 99%

“… 13 A second study, analysing mRNA and miRNA from brain tissue of 132 and 135 individuals, respectively, did not identify any individual miRNAs or mRNAs associated with surgical outcomes; however, several signalling and metabolic pathways associated with seizure recurrence were significantly enriched. 12 This suggests that a collection of smaller and coordinated effects on the transcriptome could contribute to surgical outcome.…”

Section: Introductionmentioning

confidence: 99%

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Molecular subtypes of epilepsy associated with post-surgical seizure recurrence

Hershberger,

Louis,

Busch

et al. 2023

Brain Communications

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Approximately 50% of individuals who undergo resective epilepsy surgery experience seizure recurrence. The heterogenous post-operative outcomes are not fully explained by clinical, imaging, and electrophysiological variables. We hypothesized that molecular features may be useful in understanding surgical response, and that individuals with epilepsy can be classified into molecular subtypes that are associated with seizure freedom or recurrence after surgical resection. Pre-operative blood samples, brain tissue, and post-operative seizure outcomes were collected from a cohort of 40 individuals with temporal lobe epilepsy, 23 of whom experienced post-operative seizure recurrence. Messenger RNA (mRNA) and microRNA (miRNA) extracted from the blood and tissue samples were sequenced. The mRNA and miRNA expression levels from the blood and brain were each subjected to a novel clustering approach combined with multiple logistic regression to separate individuals into genetic clusters that identify novel subtypes associated with post-operative seizure outcomes. We then compared the miRNAs and mRNAs from patient blood and brain tissue that were significantly associated with each subtype to identify signatures that are similarly over- or under-represented for an outcome, and more likely to represent endophenotypes with common molecular etiology. These target miRNAs and mRNAs were further characterized by pathway analysis to assess their functional role in epilepsy. Using blood-derived miRNA and mRNA expression levels we identified two subtypes of epilepsy that were significantly associated with seizure recurrence (clusters A1 and B4) (adjusted P<.20). 551 miRNAs and 2,486 mRNAs were associated with clusters A1 and B4, respectively (adjusted P<.05). Clustering of brain-tissue mRNA expression levels revealed an additional subtype (C2) associated with seizure recurrence that had high overlap of dysregulated mRNA transcripts with Cluster B4. Clusters A1, B4, and C2 also shared significant overlap of subjects, which altogether suggests a coordinated mechanism by which miRNA and mRNA transcripts may be related to seizure recurrence. Epileptic subtypes A1, B4, and C2 reveal both known and novel miRNA and mRNA targets in seizure recurrence. Furthermore, targets identified in A1 and B4 are quantifiable in pre-operative blood samples, and could potentially serve as biomarkers for surgical resection outcomes.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular subtypes of epilepsy associated with post-surgical seizure recurrence

Hershberger,

Louis,

Busch

et al. 2023

Brain Communications

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“…Numerous studies have explored predictors of seizure-related outcomes in different types of surgeries using non-invasive and invasive electroclinical data 2,32,46,47 . While there is a continuing effort to account for transcriptomics, single nucleotide polymorphism, and somatic variant data with regard to postsurgical outcome predictions [48][49][50] , clinically accessible germline genetic etiology has received little attention. In our multivariable analysis adjusting for the known predictors of outcome, genetic etiology was a significant factor affecting the cumulative 5-year risk of seizure recurrence.…”

Section: 10mentioning

confidence: 99%

Evaluating Clinical Presentation and Long-Term Outcomes in Individuals with Genetic and Non-Genetic Epilepsy Treated with Epilepsy Surgery: A Single-Center Study

Ivaniuk,

Boßelmann,

Pestana-Knight

et al. 2023

Preprint

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BackgroundMany genetic epilepsy disorders are characterized by focal epilepsy or exhibit focal or lateralized features, which make individuals with such conditions potential surgical candidates. However, surgical outcomes in epilepsy caused by germline genetic variants and value of genetic testing in presurgical assessment remains unclear.MethodsThis retrospective cross-sectional study included people with germline genetic epilepsy and non-genetic epilepsy identified among 2879 people with epilepsy who underwent resective surgery or laser ablation at Cleveland Clinic in years 1997-2022. We separated individuals with germline genetic epilepsies into mTORopathies (clinically or genetically diagnosed tuberous sclerosis and genetically diagnosed GATOR-related epilepsies) and other genetic etiologies. We compared clinical variables between the groups using Kruskal-Wallis and Fisher tests as appropriate. We analyzed cumulative seizure recurrence risk over 5 years with Kaplan-Meier curves and used Cox proportional hazards model for univariate and multivariate analysis. We repeated the analysis after matching both genetic sub-groups to non-genetic group 1:1 by propensity scores estimated by a generalized linear model.ResultsWe included 49 individuals with genetic epilepsies (32 individuals with mTORopathies and 17 individuals with other genetic etiologies) and 585 individuals with non-genetic epilepsy. Individuals with genetic epilepsies in both groups were younger at seizure onset (p<0.001) and at surgery (p<0.001), had a higher preoperative seizure frequency (p<0.001), higher rate of developmental delay (p<0.001), lower rate of focal interictal (p=0.005) and ictal (p<0.001) findings on EEG, and more extratemporal and extensive resections (p<0.001). At the last follow-up, individuals with other genetic etiologies had a lower rate of seizure freedom than individuals with mTORopathies and non-genetic etiologies; still, 70.6% achieved seizure reduction. Individuals with other genetic etiologies had a higher cumulative risk of seizure recurrence at 5 years both in univariate (HR 3.07, 95% CI 1.4-6.74) and multivariate (HR 3.81, 95% CI 1.69-8.62, p=0.001) analyses, which was reproducible in a matched cohort analysis.ConclusionsPeople with germline genetic epilepsy across multiple etiologies could be surgical candidates. However, seizure recurrence may be faster in genetic epilepsies other than mTORopathies. Further studies are required to clarify surgical candidacy in different genetic epilepsy disorders and establish value of presurgical genetic testing.

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