Transcriptomic profiling unveils novel therapeutic options for drug-resistant temporal lobe epilepsy.

MicroRNAs (miRNAs) are small noncoding RNAs that have emerged as new potential epigenetic biomarkers. Here, we evaluate the efficacy of six circulating miRNA previously described in the literature as biomarkers for the diagnosis of temporal lobe epilepsy (TLE) and/or as predictive biomarkers to antiepileptic drug response. We measured the differences in serum miRNA levels by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays in a cohort of 27 patients (14 women and 13 men; mean ± SD age: 43.65 ± 17.07) with TLE compared to 20 healthy controls (HC) matched for sex, age and ethnicity (11 women and 9 men; mean ± SD age: 47.5 ± 9.1). Additionally, patients were classified according to whether they had drug-responsive (n = 17) or drug-resistant (n = 10) TLE. We have investigated any correlations between miRNAs and several electroclinical parameters. Three miRNAs (miR-142, miR-146a, miR-223) were significantly upregulated in patients (expressed as average expression ± SD). In detail, miR-142 expression was 0.40 ± 0.29 vs. 0.16 ± 0.10 in TLE patients compared to HC (t-test, p < 0.01), miR-146a expression was 0.15 ± 0.11 vs. 0.07 ± 0.04 (t-test, p < 0.05), and miR-223 expression was 6.21 ± 3.65 vs. 1.23 ± 0.84 (t-test, p < 0.001). Moreover, results obtained from a logistic regression model showed the good performance of miR-142 and miR-223 in distinguishing drug-sensitive vs. drug-resistant TLE. The results of this pilot study give evidence that miRNAs are suitable targets in TLE and offer the rationale for further confirmation studies in larger epilepsy cohorts.

Epilepsy animal models indicate pronounced changes in the expression and rearrangement of GABAA receptor subunits in the hippocampus and in para-hippocampal areas, including widespread downregulation of the subunits α5 and δ, and upregulation of α4, subunits that mediate tonic inhibition of GABA. In this case–control study, we investigated changes in the expression of subunits α4, α5 and δ in hippocampal specimens of drug resistant temporal lobe epilepsy patients who underwent epilepsy surgery. Using in situ hybridization, immunohistochemistry and α5-specific receptor autoradiography, we characterized expression of the receptor subunits in specimens from patients with and without Ammon’s horn sclerosis compared to post-mortem controls. Expression of the α5-subunit was abundant throughout all subfields of the hippocampus, including the dentate gyrus, sectors CA1 and CA3, the subiculum and pre- and parasubiculum. Significant but weaker expression was detected for subunits α4 and δ notably in the granule cell/molecular layer of control specimens, but was faint in the other parts of the hippocampus. Expression of all three subunits was similarly altered in sclerotic and non-sclerotic specimens. Respective mRNA levels were increased by about 50–80% in the granule cell layer compared with post-mortem controls. Subunit α5 mRNA levels and immunoreactivities were also increased in the sector CA3 and in the subiculum. Autoradiography for α5-containing receptors using [3H]L-655,708 as ligand showed significantly increased binding in the molecular layer of the dentate gyrus in non-sclerotic specimens. Increased expression of the α5 and δ subunits is in contrast to the previously observed downregulation of these subunits in different epilepsy models, whereas increased expression of α4 in temporal lobe epilepsy patients is consistent with that in the rodent models. Our findings indicate increased tonic inhibition likely representing an endogenous anticonvulsive mechanism in temporal lobe epilepsy.

Volume of hippocampal activation as a determining factor for the lateralisation of the epileptogenic zone in patients with drug-resistant mesial temporal lobe epilepsy

Epilepsy surgery in drug resistant temporal lobe epilepsy associated with neuronal antibodies

Objective: Drug-resistant temporal lobe epilepsy (TLE) is a neurological disorder characterized by cognitive deficits. This study examined whether patients with TLE and different cognitive phenotypes differ in cortisol levels and affectivity while controlling for demographic and clinical variables. Methods: In this cross-sectional study, 79 adults with TLE underwent neuropsychological evaluation in which memory, language, attention/processing speed, executive function, and affectivity were assessed. Six saliva samples were collected in the afternoon to examine the ability of the hypothalamic-pituitary-adrenal (HPA) axis to descend according to the circadian rhythm (C1 to C6). The cortisol area under the curve concerning ground (AUCg) was computed to examine global cortisol secretion. Results: Three cognitive phenotypes were identified: memory impairment, generalized impairment, and no impairment. The memory-impairment phenotype showed higher cortisol levels at C4, C5, and C6 than the other groups (p = 0.03, η2 = 0.06), higher cortisol AUCg than the generalized-impairment phenotype (p = 0.004, η2 = 0.14), and a significant reduction in positive affectivity after the evaluation (p = 0.026, η2 = 0.11). Higher cortisol AUCg and reductions in positive affectivity were significant predictors of the memory-impairment phenotype (p < 0.001; Cox and Snell R2 = 0.47). Conclusions: Patients with memory impairment had a slower decline in cortisol levels in the afternoon, which could be interpreted as an inability of the HPA axis to inhibit itself. Thus, chronic stress may influence hippocampus-dependent cognitive function more than other cognitive functions in patients with TLE.

BackgroundP-glycoprotein (P-gp) is an efflux transporter which is abundantly expressed at the blood-brain barrier (BBB) and which has been implicated in the pathophysiology of various brain diseases. The radiolabelled antiemetic drug [11C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [11C]metoclopramide can detect increased P-gp function in the human brain, we employed drug-resistant temporal lobe epilepsy (TLE) as a model disease with a well characterised, regional P-gp up-regulation at the BBB.MethodsEight patients with drug-resistant (DRE) TLE, 5 seizure-free patients with drug-sensitive (DSE) focal epilepsy, and 15 healthy subjects underwent brain PET imaging with [11C]metoclopramide on a fully-integrated PET/MRI system. Concurrent with PET, arterial blood sampling was performed to generate a metabolite-corrected arterial plasma input function for kinetic modelling. The choroid plexus was outmasked on the PET images to remove signal contamination from the neighbouring hippocampus. Using a brain atlas, 10 temporal lobe sub-regions were defined and analysed with a 1-tissue-2-rate constant compartmental model to estimate the rate constants for radiotracer transfer from plasma to brain (K1) and from brain to plasma (k2), and the total volume of distribution (VT = K1/k2).ResultsDRE patients but not DSE patients showed significantly higher k2 values and a trend towards lower VT values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (k2: hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%).Conclusions[11C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant k2 seems to be the most sensitive parameter to measure increased P-gp function with [11C]metoclopramide. Our study provides evidence that disease-induced alterations in P-gp expression at the BBB can lead to changes in the distribution of a central nervous system-active drug to the human brain, which could affect the efficacy and/or safety of drugs. [11C]Metoclopramide PET may be used to assess or predict the contribution of increased P-gp function to drug resistance and disease pathophysiology in various brain diseases.Trial registrationEudraCT 2019-003137-42. Registered 28 February 2020.

Memory deficits are very frequent in patients with drug-resistant epilepsy, but they predict a small proportion of variance of their quality of life (QOL) in previous studies, possibly due to the lack of consideration of mediating factors of this relationship. This study aimed to examine whether trait anxiety mediates the relationship between memory and QOL in this population, controlling the influence of demographic and seizure-related factors. In this cross-sectional study, 119 adults with drug-resistant temporal lobe epilepsy (TLE) underwent a neuropsychological evaluation, in which memory, anxiety, and QOL were assessed. In the total sample, better delayed memory had an effect on better QOL indirectly through lower trait anxiety (B = 0.13, SE = 0.06, p = 0.04, abcs = 0.13; κ2 = 0.18; PMind = 0.76). Additionally, delayed memory has not a direct association with QOL (B = 0.04, SE = 0.09, p = 0.64, Cohen's f2 = 0.005; PMdir = 0.24), and the total effect of delayed memory on QOL tended to reach statistical significance (B = 0.17, SE = 0.10, p = 0.08). The proposed mediation model yielded excellent fit (CFI = 1.00, RMSEA = 0.0001, SRMR = 0.009, and χ2 (1) = 0.50, p = 0.48) and explained 38% of the variance of QOL. These findings suggest that trait anxiety is an important factor in understanding the relationship between memory and QOL in patients with TLE, considering the influence of demographic and seizure-related variables, and may have relevant implications for decision-making in this population.

Pathological amyloid-β (Aβ) accumulation and hyperphosphorylated tau proteins have been described in resected temporal lobe specimens of epilepsy patients. We aimed to determine cerebrospinal fluid (CSF) Aβ1-42 and p181-tau levels and cerebral Aβ deposits on positron emission tomography (Aβ PET) and correlate these findings with cognitive performance in adults with drug-resistant temporal lobe epilepsy (TLE). In this cross-sectional study, we enrolled individuals with drug-resistant TLE who were 25-55 years old. Each participant underwent 18F-flutemetamol PET, determination of CSF Aβ1-42, p181-tau, and total tau, and a comprehensive neuropsychological assessment. We evaluated normalized standard uptake value ratios (SUVRs) for different brain regions on Aβ PET. Thirty patients (mean age = 41.9 ± SD 8.1 years, 57% men) were included. The median disease duration was 9.5 (interquartile range = 4-24) years. Twenty-six patients (87%) had a clinically significant cognitive impairment on neuropsychological evaluation, 18 (69%) of the amnesic type. On Aβ PET, high uptake was observed in both mesial temporal regions (ipsilateral: SUVR z-score = .90, 95% confidence interval [CI] = .60-1.20; contralateral: SUVR z-score = .92, 95% CI = .57-1.27; p < .001), which was higher when compared to SUVR z-scores in all the remaining regions (p < .001) and in the ipsilateral anterior cingulate (SUVR z-score = .27, 95% CI = .04-.49, p = .020). No significant deposition was observed in other regions. Seven patients (23%) had low Aβ1-42 levels, and two (7%) had elevated p181-tau levels in CSF. Higher p181-tau levels correlated with poorer verbal fluency (R = -.427, p = .044). Our findings reveal a considerable Aβ deposition in mesial temporal regions and ipsilateral anterior cingulate among adults with drug-resistant TLE. Additionally, abnormal CSF Aβ1-42 levels were observed in a significant proportion of patients, and p181-tau levels were associated with verbal fluency. These results suggest that markers of neuronal damage can be observed in adults with TLE, warranting further investigation.

Progression of Amyloid Accumulation in Late Adulthood Among People With Childhood-Onset Epilepsy. Joutsa J, Rinne JO, Niemi KJ, Karrasch M, Parkkola RK, Saunavaara J, Helin SP, Hermann BP, Sillanpää M. Neurology. 2025;104(3):e210303. doi: 10.1212/WNL.0000000000210303 . Background and objectives: Previous research has demonstrated increased brain amyloid plaque load in individuals with childhood-onset epilepsy in late middle age. However, the trajectory of this process is not yet known. The aim of this study was to determine whether individuals with a history of childhood-onset epilepsy show progressive brain aging in amyloid accumulation in late adulthood (Turku Adult Childhood-Onset Epilepsy study, TACOE). Methods: Adults from a prospective population-based cohort of individuals with childhood-onset epilepsy, originally recruited 1961-1964, together with matched controls, were scanned with [ 11 C]PIB PET twice: after at least 50 years (TACOE-50) and again after at least 55 years (TACOE-55) from the diagnosis. Results: At TACOE-55, 31.4% (11/36, mean age 63.3 years, 52.8% female) of individuals from the epilepsy group and 11.4% (4/35, 63.1 year, 54.3%) of controls had a visually abnormal [ 11 C]PIB scan ( p = 0.039). At TACOE-55, cortical brain [ 11 C]PIB uptakes were higher and increased more from TACOE-50 in the epilepsy compared with the control group ( p &lt; 0.05). In voxelwise whole-brain analyses, the epilepsy group showed significantly higher and more widespread brain amyloid accumulation ( p FWE &lt; 0.05). Discussion: The results demonstrate that childhood-onset epilepsy is associated with an earlier age at onset of amyloidosis and greater progressive amyloid accumulation in late adulthood. Amyloid deposition in adults with drug-resistant temporal lobe epilepsy Fonseca E, Lallana S, Ortega G, Cano A, Sarria-Estrada S, Pareto D, Quintana M, Lorenzo-Bosquet C, López-Maza S, Gifreu A, Campos-Fernández D, Abraira L, Santamarina E, Orellana A, Montrreal L, Puerta R, Aguilera N, Ramis M, de Rojas I, Ruiz A, Tárraga L, Rovira À, Marquié M, Boada M, Toledo M. Epilepsia. 2024 Dec;65(12):3664–3675. doi: 10.1111/epi.18142 . Objective: Pathological amyloid-β (Aβ) accumulation and hyperphosphorylated tau proteins have been described in resected temporal lobe specimens of epilepsy patients. We aimed to determine cerebrospinal fluid (CSF) Aβ1–42 and p181-tau levels and cerebral Aβ deposits on positron emission tomography (Aβ PET) and correlate these findings with cognitive performance in adults with drug-resistant temporal lobe epilepsy (TLE). Methods: In this cross-sectional study, we enrolled individuals with drug-resistant TLE who were 25–55 years old. Each participant underwent 18 F-flutemetamol PET, determination of CSF Aβ1–42, p181-tau, and total tau, and a comprehensive neuropsychological assessment. We evaluated normalized standard uptake value ratios (SUVRs) for different brain regions on Aβ PET. Results: Thirty patients (mean age = 41.9 ± SD 8.1 years, 57% men) were included. The median disease duration was 9.5 (interquartile range = 4–24) years. Twenty-six patients (87%) had a clinically significant cognitive impairment on neuropsychological evaluation, 18 (69%) of the amnesic type. On Aβ PET, high uptake was observed in both mesial temporal regions (ipsilateral: SUVR z -score = .90, 95% confidence interval [CI] = .60–1.20; contralateral: SUVR z -score = .92, 95% CI = .57–1.27; p &lt; .001), which was higher when compared to SUVR z -scores in all the remaining regions ( p &lt; .001) and in the ipsilateral anterior cingulate (SUVR z -score = .27, 95% CI = .04–.49, p = .020). No significant deposition was observed in other regions. Seven patients (23%) had low Aβ1–42 levels, and two (7%) had elevated p181-tau levels in CSF. Higher p181-tau levels correlated with poorer verbal fluency ( R = −.427, p = .044). Significance: Our findings reveal a considerable Aβ deposition in mesial temporal regions and ipsilateral anterior cingulate among adults with drug-resistant TLE. Additionally, abnormal CSF Aβ1–42 levels were observed in a significant proportion of patients, and p181-tau levels were associated with verbal fluency. These results suggest that markers of neuronal damage can be observed in adults with TLE, warranting further investigation.

Neuropsychological tests with lateralizing value in patients with temporal lobe epilepsy: Reconsidering material-specific theory

Successful management of postictal violence with pindolol in temporal lobe epilepsy.

Objective: To analyse the long term results of temporal lobe epilepsy surgery in a national epilepsy surgery centre for adults, and to evaluate preoperative factors predicting a good postoperative outcome...

IntroductionEpilepsy is closely related to daily rhythms, such as the sleep–wake cycle. The objective of this study was to evaluate the relationship between drug-resistant temporal lobe epilepsy (TLE) and the...

Surgery is an effective but costly treatment for many patients with drug-resistant temporal lobe epilepsy (DR-TLE). We aim to evaluate whether, in the United States, surgery is cost-effective compared to medical management for patients deemed surgical candidates and whether surgical evaluation is cost-effective for patients with DR-TLE in general. We use a semi-Markov model to assess the cost-effectiveness of surgery and surgical evaluation over a lifetime horizon. We use second-order Monte Carlo simulations to conduct probabilistic sensitivity analyses to estimate variation in model output. We adopt both health care and societal perspectives, including direct health care costs (e.g., surgery, antiepileptic drugs) and indirect costs (e.g., lost earnings by patients and care providers.) We compare the incremental cost-effectiveness ratio to societal willingness to pay (∼$100,000 per quality-adjusted life-year [QALY]) to determine whether surgery is cost-effective. Epilepsy surgery is cost-effective compared to medical management in surgically eligible patients by virtue of being cost-saving ($328,000 vs $423,000) and more effective (16.6 vs 13.6 QALY) than medical management in the long run. Surgical evaluation is cost-effective in patients with DR-TLE even if the probability of being deemed a surgical candidate is only 5%. From a societal perspective, surgery becomes cost-effective within 3 years, and 89% of simulations favor surgery over the lifetime horizon. For surgically eligible patients with DR-TLE, surgery is cost-effective. For patients with DR-TLE in general, referral for surgical evaluation (and possible subsequent surgery) is cost-effective. Patients with DR-TLE should be referred for surgical evaluation without hesitation on cost-effectiveness grounds.

Neurological disorder can cause functional network changes in white matter (WM). However, changes in the WM functional network in children with drug-resistant temporal lobe epilepsy (DRTLE) require further clarification. Therefore, we combine graph theory with resting-state functional magnetic resonance imaging (rs-fMRI) and T1-weighted imaging (T1WI) to investigate the topological features of the WM network in children with DRTLE, discover potential biomarkers, and understand the underlying neurological mechanisms. We included 91 children (43 with DRTLE and 48 healthy controls), acquiring structural and functional MRI data to construct WM functional networks. Graph theory was applied to evaluate topological differences and their correlation with onset age, disease duration and cognitive measures. A Support Vector Machine model classified individuals with DRTLE based on WM connectivity, with accuracy validated through leave-one-out cross-validation. The global topological properties of the WM network in children with DRTLE were altered, manifesting as an imbalance between global integration and segregation Local nodal efficiency changes in the association fibers exhibited reduced information transfer and centrality at several nodes. Conversely, commissural and projection fibers displayed increased network properties. Cognitive metrics correlated with nodal disturbances. The classification model achieved 73.6 % accuracy and an area under the curve (AUC) of 0.744. This indicates that the WM functional network in DRTLE presents with anomalies in the topological attributes, which are associated with cognitive impairments. The WM functional connectivity may serve as valuable indicators for clinical classification of the condition. The insights provided have augmented our understanding of the complex neurological mechanisms involved in epilepsy.