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Objective: In temporal lobe epilepsy (TLE), a taxonomy classifying patients into 3 cognitive phenotypes has been adopted: minimally, focally, or multidomain cognitively impaired (CI). We examined gray matter (GM) thickness patterns of cognitive phenotypes in drug‐resistant TLE and assessed potential use for predicting postsurgical cognitive outcomes. Methods: TLE patients undergoing presurgical evaluation were categorized into cognitive phenotypes. Network edge weights and distances were calculated using type III analysis of variance F‐statistics from comparisons of GM regions within each TLE cognitive phenotype and age‐ and sex‐matched healthy participants. In resected patients, logistic regression models (LRMs) based on network analysis results were used for prediction of postsurgical cognitive outcome. Results: A total of 124 patients (63 females, mean age ± standard deviation [SD] = 36.0 ± 12.0 years) and 117 healthy controls (63 females, mean age ± SD = 36.1 ± 12.0 years) were analyzed. In the multidomain CI group (n = 66, 53.2%), 28 GM regions were significantly thinner compared to healthy controls. Focally impaired patients (n = 37, 29.8%) showed 13 regions, whereas minimally impaired patients (n = 21, 16.9%) had 2 significantly thinner GM regions. Regions affected in both multidomain and focally impaired patients included the anterior cingulate cortex, medial prefrontal cortex, medial temporal, and lateral temporal regions. In 69 (35 females, mean age ± SD = 33.6 ± 18.0 years) patients who underwent surgery, LRMs based on network‐identified GM regions predicted postsurgical verbal memory worsening with a receiver operating curve area under the curve of 0.70 ± 0.15. Interpretation: A differential pattern of GM thickness can be found across different cognitive phenotypes in TLE. Including magnetic resonance imaging with clinical measures associated with cognitive profiles has potential in predicting postsurgical cognitive outcomes in drug‐resistant TLE. ANN NEUROL 2024;95:984–997 [ABSTRACT FROM AUTHOR]

Background and purpose: In patients with epilepsy and sustained seizure freedom, guidelines recommend considering discontinuation of antiseizure medication (ASM) based on shared decision‐making. This study aims to identify factors associated with non‐discontinuation of ASM in seizure‐free patients. Methods: Retrospective data from three sites of an academic outpatient clinic were analyzed. Adult patients with epilepsy who have been seizure‐free for ≥24 months on ASM monotherapy were included. The primary end‐point was non‐discontinuation of ASM, defined as no discontinuation or no dose reduction of ≥25% at the last outpatient clinic visit in the ultimate seizure‐free interval. Secondary end‐points included frequency of discussion on discontinuation attempts between patients and physicians, adherence to ASM discontinuation decisions, and post‐discontinuation seizure outcomes. Results: Out of 338 included patients, 81.7% did not discontinue ASM and did not reduce its dose, 11.5% discontinued ASM and 6.8% had a significant dose reduction. Factors independently associated with non‐discontinuation of ASM were history of focal to bilateral or generalized tonic–clonic seizures (odds ratio [OR] 2.33, 95% confidence interval [CI] 1.08–5.06), history of breakthrough seizures (OR 3.32, 95% CI 1.10–10.04), history of failed attempts to discontinue or reduce the ASM dose (OR 4.67, 95% CI 1.03–21.11) and higher ASM load at the index visit (OR 6.10, 95% CI 2.09–17.78). Discontinuation attempts were made during the entire period of seizure freedom and were most commonly undertaken ≥10 years after the last seizure. Conclusions: This study provides insights into factors associated with the shared decision‐making process regarding ASM discontinuation in seizure‐free patients and highlights the importance of considering individual patient characteristics and seizure history. [ABSTRACT FROM AUTHOR]

Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K+ efflux as a key signaling event, suggesting that K+-permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K+ channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown. Using a novel specific inhibitor of THIK-1 in combination with patch-clamp electrophysiology in slices of human neocortex, we found that THIK-1 generated the main tonic K+ conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K+ efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demonstrated that activation of P2X7 was mandatory for ATP-evoked IL-1β release, which was strongly suppressed by blocking THIK-1. Surprisingly, THIK-1 contributed only marginally to the total K+ conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K+-independent mechanism of THIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective expression of THIK-1 in human brain microglia, while P2X7 had a much broader expression. Thus, inhibition of THIK-1 could be an effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinflammation. [ABSTRACT FROM AUTHOR]

• Focal electroclinical features at onset of generalized seizure are well-known. • In contrary, knowledge on generalized onset seizures with focal evolution is sparse. • We report detailed ictal EEG and semiological characteristics of five such patients. • As focal signs may be prominent, risk of misclassification as focal seizure is high. • In generalized onset seizures, focal electroclinical features seem to be a variant. At onset of generalized seizures, focal electroclinical features are commonly seen, while generalized onset seizures with focal evolution (GOFE) are largely unknown bearing the risk of misclassification. In two German epilepsy-centers, patients with GOFE documented by video-EEG monitoring (VEM) between 2017 and 2022 were identified retrospectively. In addition to analysis of ictal electroclinical features, detailed epilepsy and family history, response to antiseizure medication (ASM), and findings from neuroimaging were considered. We identified five patients with GOFE, three females, age 14 to 22 years. All patients developed genetic generalized epilepsy in childhood or adolescence, each presenting with two or three generalized seizure types. In each of the five patients, one GOFE was recorded by VEM. At onset, EEG seizure patterns were characterized by generalized spike-wave discharges at 2.5 to 3.5/ sec for 9 to 16 s followed by focal evolution of the discharges. Interictally, all patients presented with generalized spike-wave discharges without focal abnormalities. Semiology at onset was behavioral arrest in two patients and generalized increase in tone in one, while two onsets were clinically inapparent. Semiological signs during focal evolution were variable, comprising head and body version, figure 4 sign, unilateral arm clonic activity, and staring with oral automatisms. In one case, focality involved both hemispheres successively. Prominent focal semiological features in GOFE carry a high risk of misclassification as focal seizures and epilepsy and thus wrong choice of ASM. This calls for low-threshold VEM if any doubts of focal genesis of seizures exist. [ABSTRACT FROM AUTHOR]

Objective: Epilepsy with generalized tonic–clonic seizures alone (GTCA) is a common but poorly characterized idiopathic generalized epilepsy (IGE) syndrome. Hence, we investigated electroclinical features, seizure outcome, and antiseizure medication (ASM) withdrawal in a large cohort of GTCA patients. Methods: In this multicenter retrospective study, GTCA patients defined according to the diagnostic criteria of the International League Against Epilepsy (2022) were included. We investigated prognostic patterns, drug resistance at the last visit, and ASM withdrawal, along with their prognostic factors. Results: We included 247 patients with a median (interquartile range [IQR]) age at onset of 17 years (13–22) and a median follow‐up duration of 10 years (IQR = 5–20). Drug resistance at the last visit was observed in 40 (16.3%) patients, whereas the median latency to achieve 2‐year remission was 24 months (IQR = 24–46.5) with a median number of 1 (IQR = 1–2) ASM. During the long‐term follow‐up (i.e., 202 patients followed ≥5‐years after the first ASM trial), 69 (34.3%) patients displayed an early remission pattern and 36 (17.9%) patients displayed a late remission pattern, whereas 16 (8%) and 73 (36.3%) individuals had no‐remission and relapsing–remitting patterns, respectively. Catamenial seizures and morning predominance of generalized tonic–clonic seizures (GTCS) independently predicted drug resistance at the last visit according to multivariable logistic regression. Treatment withdrawal was attempted in 63 (25.5%) patients, with 59 (93.7%) of them having at least a 12‐month follow‐up after ASM discontinuation. At the last visit, 49 (83%) of those patients had experienced GTCS recurrence. A longer duration of seizure freedom was the only factor predicting a higher chance of successful ASM withdrawal according to multivariable Cox regression. Significance: GTCA could be considered a relatively easily manageable IGE syndrome, with a low rate of drug resistance and a high prevalence of early response to treatment. Nevertheless, a considerable proportion of patients experience relapsing patterns of seizure control, highlighting the need for appropriate counseling and lifestyle recommendations. [ABSTRACT FROM AUTHOR]

Background: Antiseizure medications can have negative effects on plasma lipid levels. Objectives: To evaluate plasma lipid changes in patients with newly diagnosed focal epilepsy treated with eslicarbazepine acetate (ESL) or controlled-release carbamazepine (CBZ-CR) monotherapy during a phase III, randomized, double-blind (DB) trial and 2 years of ESL treatment in an open-label extension (OLE). Design: Post hoc analysis of a phase III trial and OLE study. Methods: Proportions of patients with elevated levels of total cholesterol and low-density lipoprotein (LDL) cholesterol were assessed at DB baseline, OLE baseline (last visit of DB trial), and end of OLE. Results: A total of 184 patients received ESL monotherapy during the OLE: 96 received ESL monotherapy in the DB trial and 88 patients received CBZ-CR monotherapy. The proportions of patients with elevated total cholesterol and LDL cholesterol increased significantly during the DB trial in those treated with CBZ-CR monotherapy [total cholesterol, +14.9% (p < 0.001); LDL cholesterol, +11.5% (p = 0.012)] but decreased significantly after switching to ESL monotherapy in the OLE [total cholesterol, −15.3% (p = 0.008); LDL cholesterol, −11.1% (p = 0.021)]. No significant changes were observed in those treated with ESL monotherapy during the DB trial and OLE. At the end of the DB trial, between-group differences (ESL–CBZ-CR) in the proportions of patients with elevated total and LDL cholesterol were −13.6% (p = 0.037) and −12.3% (p = 0.061), respectively; at the end of the OLE, these between-group differences were −6.0% (p = 0.360) and −0.6% (p = 1.000), respectively. Conclusion: A lower proportion of patients with newly diagnosed focal epilepsy had increased levels of total and LDL cholesterol, compared to baseline, following monotherapy with ESL versus CBZ-CR; after switching from CBZ-CR to ESL, the proportions of patients with increased levels decreased significantly. Registration: ClinicalTrials.gov NCT01162460/NCT02484001; EudraCT 2009-011135-13/2015-001243-36. Plain language summary The impact of treatment with either eslicarbazepine acetate or controlled-release carbamazepine on cholesterol levels in patients with newly diagnosed focal epilepsy Patients with epilepsy have an increased risk of having cardiovascular and cerebrovascular diseases (e.g., myocardial infarction and stroke). Treatment with antiseizure medications can have a negative effect on blood cholesterol levels [such as total cholesterol and low-density lipoprotein (LDL) cholesterol], which can further increase the risk of cardiovascular and cerebrovascular diseases. We examined the impact of monotherapy treatment (i.e., treatment with only one antiseizure medication) using either eslicarbazepine acetate (ESL) or a controlled-release formulation of carbamazepine (CBZ-CR) in 184 patients with newly diagnosed focal epilepsy (ESL, 96 patients; CBZ-CR, 88 patients). Patients received monotherapy with ESL or CBZ-CR for approximately 1 year in a phase III clinical trial. After this, the patients could continue into a 2-year extension study during which they all received monotherapy with ESL. We assessed the proportions of patients with elevated levels of total cholesterol and LDL cholesterol at the beginning and end of the phase III trial, and at the end of the extension study. At the beginning of the phase III trial, the proportions of patients with elevated total cholesterol and elevated LDL cholesterol were similar between treatment groups. During the phase III trial, the proportions of patients with elevated total cholesterol and elevated LDL cholesterol increased in those treated with CBZ-CR monotherapy (total cholesterol, +14.9%; LDL cholesterol, +11.5%) but decreased after switching to ESL monotherapy in the extension study (total cholesterol, −15.3%; LDL cholesterol, −11.1%). By contrast, the proportions of patients with elevated levels of total cholesterol and LDL cholesterol remained relatively stable in those treated with ESL monotherapy during the phase III trial and extension study. These findings indicate that ESL monotherapy may be an appropriate treatment option for patients with newly diagnosed focal epilepsy who either already have, or who are at risk of developing, high levels of cholesterol, since this may reduce their likelihood of having cardiovascular and cerebrovascular diseases. [ABSTRACT FROM AUTHOR]

Objective: To investigate cost in working hours for initial integration of interictal EEG source localization (ESL) into clinical practice of a tertiary epilepsy center, and to examine concordance of results obtained with three different ESL pipelines. Methods: This prospective study covered the first year of using ESL in the Epilepsy‐Center Berlin‐Brandenburg. Patients aged ≥14 years with drug‐resistant focal epilepsy referred for noninvasive presurgical evaluation were included. Interictal ESL was based on low‐density EEG and individual head models. Source maxima were obtained from two freely available software packages and one commercial provider. One physician and computer scientist documented their working hours for setting up and processing ESL. Additionally, a survey was conducted among epilepsy centers in Germany to assess the current role of ESL in presurgical evaluation. Results: Of 40 patients included, 22 (55%) had enough interictal spikes for ESL. The physician's working times decreased from median 4.7 hours [interquartile range 3.9‐6.4] in the first third of cases to 2.0 hours [1.9‐2.4] in the remaining two thirds; P < 0.01. In addition, computer scientist and physician spent a total of 35.5 and 33.0 working hours on setting up the digital infrastructure, and on training and testing. Sublobar agreement between all three pipelines was 20%, mean measurement of agreement (kappa) 0.13. Finally, the survey revealed that 53% of epilepsy centers in Germany currently use ESL for presurgical evaluation. Significance: This study provides information regarding expected effort and costs for integration of ESL into an epilepsy surgery program. Low result agreement across different ESL pipelines calls for further standardization. [ABSTRACT FROM AUTHOR]

Introduction: The increasing identification of specific autoantibodies against brain structures allows further refinement of the group of autoimmune-associated epilepsies and affects diagnostic and therapeutic algorithms. The early etiological allocation of a first seizure is particularly challenging, and the contribution of cerebrospinal fluid (CSF) analysis is not fully understood. Methods: In this retrospective study with a mean of 7.8 years follow-up involving 39 well-characterized patients with the initial diagnosis of new-onset seizure or epilepsy of unknown etiology and 24 controls, we determined the frequency of autoantibodies to brain proteins in CSF/serum pairs using cell-based assays and unbiased immunofluorescence staining of unfixed murine brain sections. Results: Autoantibodies were detected in the CSF of 30.8% of patients. Underlying antigens involved glial fibrillary acidic protein (GFAP) and N-methyl-D-aspartate (NMDA) receptors, but also a range of yet undetermined epitopes on neurons, glial and vascular cells. While antibody-positive patients had higher frequencies of cancer, they did not differ from antibody-negative patients with respect to seizure type, electroencephalography (EEG) and cranial magnetic resonance imaging (cMRI) findings, neuropsychiatric comorbidities or pre-existing autoimmune diseases. In 5.1% of patients with seizures or epilepsy of initially presumed unknown etiology, mostly CSF findings resulted in etiological reallocation as autoimmune-associated epilepy. Discussion: These findings strengthen the potential role for routine CSF analysis. Further studies are needed to understand the autoantibody contribution to etiologically unclear epilepsies, including determining the antigenic targets of underlying autoantibodies. [ABSTRACT FROM AUTHOR]

Objective: Many people with epilepsy report subjective cognitive impairment (SCI), i.e., problems with memory, attention, or executive functions, reducing quality of life. Nevertheless, overlap with objective cognitive impairment (OCI) is often weak. One reason may be a domain‐specific mismatch between subjective reports and objective tests. We aimed to evaluate relations between SCI and OCI of corresponding domains and to assess whether these differ between persons who over‐ or underestimate their performance. Methods: In this prospective, cross‐sectional sample of 104 adult inpatients with epilepsy, we performed multiple regression analyses predicting SCI in the domains attention, memory, and executive functions. We tested relationships with measures of psychomotor speed, short‐term memory, verbal learning, verbal delayed recall, and word fluency while controlling for age, sex, seizure frequency, structural lesions, mono‐ versus polytherapy and adverse events of antiseizure medication (ASM), depressive and anxiety symptoms, level of education, and employment status. Furthermore, we tested whether these relationships differed between realistic raters and over‐ and underestimators. Results: We found domain‐specific relations for attention and executive functions for the full sample, explaining a small proportion of variance of SCI (general dominance index =.03 and.004), whereas ASM adverse events and psychological variables were more important predictors. When dividing the sample according to the concordance of SCI and OCI, we found high frequencies of both over‐ (23%–46%) and underestimation (31%–35%) depending on the domain. The explanatory power of OCI for SCI was stronger within the subgroups compared to the full sample, suggesting nonlinear relationships and different underlying mechanisms for realistic raters, underestimators, and overestimators. Significance: Domain‐specific SCI and OCI are related, and both should be assessed with standardized instruments. These relationships differ between over‐ and underestimators as well as realistic raters. Based on the concordance of self‐ratings and objective measures, tailored counseling and treatment should be offered. [ABSTRACT FROM AUTHOR]

In Germany, long-term video EEG as the gold standard for the diagnostics of epilepsy and other seizure disorders, is currently only available for inpatient monitoring in a limited number of specialized centers. These limited monitoring capacities and the large amount of associated time and work resources lead to a significant waiting time for this important diagnostic procedure nationwide. New portable sensor technology and automated data analysis methods are creating opportunities for gold standard long-term video EEG assessments in outpatient settings, which may help to resolve this barrier. Here, we report the results of a single-center feasibility study by implementing outpatient long-term video EEG (ALVEEG) as a diagnostic pathway in Germany. In the new diagnostic pathway, the use of innovative, portable video EEG monitoring systems along with artificial intelligence-assisted data analysis are intended to provide those patients affected by seizure disorders with a more rapid, efficient, and cross-sectoral access to gold standard diagnostics in the home environment. The diagnostics were well accepted by patients and clinicians and may represent a complementary option to inpatient monitoring to eliminate current bottlenecks in diagnostics and care. [ABSTRACT FROM AUTHOR]