Increased body mass index (BMI) associated with late epilepsy onset in patients with temporal encephaloceles: a systematic review and analysis of individual patient data.

OBJECTIVE: This study investigates the association of Body Mass Index (BMI) and age of epilepsy onset, in patients with epilepsy associated with temporal encephaloceles (TEs). METHODS: A comprehensive PubMed literature review was conducted using the keywords "temporal encephaloceles" and "epilepsy" for identifying articles for the analysis. Inclusion criteria encompassed all evidence levels reporting patients with TE-related epilepsy and documented BMI. Logistic regression analyses were performed to examine the effect of BMI on predicting epilepsy onset after the 25th year of age. Spearman's correlation assessed the relationship between BMI with epilepsy onset. Finally, the association between BMI and postsurgical outcomes, distinguishing between more favourable outcomes (Engel Class I and II) and less favourable outcomes (Engell Class III and IV) was explored. RESULTS: Of the initially identified 88 articles, nine were included in the analysis, involving 127 patients with TE-related epilepsy and reported BMI. The mean age of epilepsy onset was 24.9 years (SD = 14.8 years), with a mean BMI of 28.0 kg/m2 (SD = 7.4 kg/m2). A significant positive correlation was observed between BMI and age of epilepsy onset (rho = 0.448, p < 0.001). Female patients had higher BMI compared to male patients (30.1 kg/m2, SD = 8.7 kg/m2 and 26.5 kg/m2, SD = 5.3 kg/m2 respectively, p = 0.008). However, the epilepsy onset did not differ significantly between male and female patients (p = 0.26). The bivariate logistic regression showed that patients with increased BMI were more likely to have an epilepsy onset after the 25th year of age, adjusted for the confounder sex (OR = 1.133, 95%-CI [1.060, 1.211], p < 0.001). Finally, a potential trend indicated a higher average BMI among patients with more favourable postsurgical outcomes than less favourable postsurgical outcomes (27.3 kg/m2, SD = 7.7 kg/m2 and 24.8 kg/m2, SD = 2.2 kg/m2 respectively, p = 0.076).

First seizure in elderly patients: Need to treat? Evidence from a retrospective study.

BACKGROUND: The risk of seizure recurrence after a first unprovoked epileptic seizure is reported to be approximately 40%. Little is known about the recurrence risk after a first seizure in elderly patients, who may be at higher risk due to an increased rate of structural lesions, encephalopathy, subcortical arteriosclerotic encephalopathy or brain atrophy. METHODS: In a retrospective approach, the recurrence rate in 304 patients aged 60 years and above who presented with a first seizure between 2004 and 2017 was analyzed. Hierarchical Cox regression was used to investigate the impact of EEG and neuroimaging results, age or the prescription of anti-seizure medication (ASM) on seizure recurrence. RESULTS: Seizure recurrence rates were 24.5% and 34.4% after one and two years, respectively. Anti-seizure medication was started in 87.8% of patients, in 28.8% despite the absence of clear epileptogenic lesions on neuroimaging or epileptiform potentials in the EEG. Medical treatment significantly reduced the risk of recurrence (hazard ratio = 0.47). Epileptiform potentials in the EEG, epileptogenic lesions in neuroimaging and age had no significant effect on seizure recurrence. Age and the presence of neurodegenerative and psychiatric comorbidities showed a significant association with ASM prescription. CONCLUSIONS: The present data show a strong protective effect of ASM on seizure recurrence in patients above the age of 60, even in the absence of pathologic neuroimaging or EEG results needed for the diagnosis of epilepsy. Treatment with ASM therefore seems beneficial for reducing the recurrence risk in elderly patients. The lack of a significant association between seizure recurrence and epileptogenic lesions might be related to other confounding factors like encephalopathy, subcortical arteriosclerotic encephalopathy, neurodegenerative diseases or brain atrophy.

First epileptic seizure and quality of life - A prospective study.

OBJECTIVE: Impaired QoL and depression are common in patients with chronic epilepsies; however, data on the impact of a first seizure on QoL are sparse. According to the current ILAE-definition of epilepsy, patients may be diagnosed with epilepsy immediately after the first seizure, if EEG and/or imaging findings are abnormal. Patients with normal findings in imaging and EEG are not diagnosed as having epilepsy. We investigated QoL in patients after a first seizure with and without a consecutive diagnosis of epilepsy to detect differences between groups within the first year after seizure. METHODS: We examined patients (n = 152) after a first epileptic seizure and six and 12 months thereafter using demographic, clinical and QoL-related questionnaire data (Short Form-36 Health Survey (SF-36), Quality of Life in Epilepsy Inventory-31 (QOLIE-31), Beck's depression inventory II (BDI-II)). RESULTS: Patients diagnosed with epilepsy after the first seizure showed a tendency of reduced mental health-related QoL six (p =.098) and 12 months (p =.092) after the first seizure compared to patients who were not diagnosed with epilepsy, but were diagnosed as having had a single first seizure. There were no significant differences between the two groups in physical health-related QoL. Multiple regression analyses showed that especially depressive symptoms explained 22.0 - 48.7 % of the variance in mental health-related QoL six (p <.001) and 12 months (p <.001) after the first seizure. Physical health-related QoL was especially predicted by age (p <.001), group (p =.002) and recurrent seizures (p = < 0.001). In PWE, there was a statistical trend with improving QOLIE-31 overall scores from six to 12 months (p =.086). CONCLUSION: Our results suggest that QoL may be impaired in patients diagnosed with epilepsy early, immediately after the onset of disease. Early follow-up monitoring from the beginning of patient career is important for possible interventions and to improve patients' daily life in the long term.

Verbal memory depends on structural hippocampal subfield volume.

Objective: To investigate correlates in hippocampal subfield volume and verbal and visual memory function in patients with temporal lobe epilepsy (TLE), mild amnestic cognitive impairment (MCI) and heathy participants (HP). Methods: 50 right-handed participants were included in this study; 11 patients with temporal lobe epilepsy (TLE), 18 patients with mild amnestic cognitive impairment (MCI) and 21 healthy participants (HP). Verbal memory performance was evaluated via the verbal memory test (VLMT) and visual memory performance via the diagnosticum for cerebral damage (DCM). Hippocampal subfield volumes of T1-weighted Magnetic Resonance Imaging (MRI) scans were computed with FreeSurfer version 7.1. Stepwise correlation analyses were performed between the left hippocampal subfield volumes and learning, free recall, consolidation and recognition performance scores of the VLMT as well as between right hippocampal subfield volumes and visual memory performance. Results: The volume of the left subicular complex was highly correlated to learning performance (ß = 0.284; p = 0.042) and free recall performance in the VLMT (ß = 0.434; p = 0.001). The volume of the left CA3 subfield showed a significant correlation to the consolidation performance in the VLMT (ß = 0.378; p = 0.006) and recognition performance in the VLMT (ß = 0.290; p = 0.037). There was no significant correlation identified between the right hippocampal subfields and the visual memory performance. Conclusion: The results of this study show verbal memory correlates with hippocampal subfields and support the role of left subiculum and left CA2/CA3 in verbal memory performance.

The phenotypic and genotypic spectrum of epilepsy and intellectual disability in adults: Implications for genetic testing.

OBJECTIVE: The phenotypic and genotypic spectrum of adult patients with epilepsy and intellectual disability (ID) is less clear than in children. We investigated an adult patient cohort to further elucidate this and inform the genetic testing approach. METHODS: Fifty-two adult patients (30 male, 22 female) with epilepsy, at least mild ID and no known genetic or acquired cause were included and phenotyped. Variants identified through exome sequencing were evaluated using ACMG criteria. Identified variants were compared with commercially available gene panels. Cluster analysis of two features, age at seizure onset and age at ascertainment of cognitive deficits, was performed. RESULTS: Median age was 27 years (range 20-57 years) with median seizure onset at 3 years and median ascertainment of cognitive deficits at 1 year. Likely pathogenic/pathogenic variants were identified in 16/52 patients (31%) including 14 (27%) single nucleotide variants and 2 (4%) copy number variants. Simulated yield of commercial gene panels varied between 13% in small (≤144 genes) and 27% in large panels (≥1478 genes). Cluster analysis (optimal number 3 clusters) identified a cluster with early seizure onset and early developmental delay (developmental and epileptic encephalopathy, n = 26), a cluster with early developmental delay but late seizure onset (ID with epilepsy, n = 16) and a third cluster with late ascertainment of cognitive deficits and variable seizure onset (n = 7). The smaller gene panels particularly missed the genes identified in the cluster with early ascertainment of cognitive deficits and later onset of epilepsy (0/4) as opposed to the cluster with developmental and epileptic encephalopathy (7/10). SIGNIFICANCE: Our data indicates that adult patients with epilepsy and ID represent a heterogeneous cohort that includes grown-up patients with DEE but also patients with primary ID and later onset of epilepsy. To maximize diagnostic yield in this cohort either large gene panels or exome sequencing should be used.

Effect of the revised definition of epilepsy on treatment decisions and seizure recurrence after a first epileptic seizure.

BACKGROUND: Studies on risk factors for epilepsy and seizure recurrence after a first seizure are usually based on the old definition of epilepsy with the need for two unprovoked seizures. The current definition of epilepsy allows diagnosis and treatment of epilepsy after a first seizure if the recurrence risk is >60%. We evaluate treatment decisions, seizure recurrence and risk factors for epilepsy related to the application of the new definition of epilepsy. METHODS: Data of 629 patients with a first seizure were analyzed to investigate changes of treatment decisions and seizure recurrence after the revised definition of epilepsy. We used binary logistic regression to investigate the impact of multiple factors influencing seizure recurrence like electroencephalogram (EEG) and magnetic resonance imaging (MRI) results and administration of antiseizure medication (ASM). RESULTS: The proportion of patients receiving ASM significantly increased from 70.4% to 80.5% (p = 0.015) following the new epilepsy definition, without any significant changes in the recurrence rate (40.8% vs. 45.5% after 2 years, p > 0.05). The presence of interictal epileptiform discharges (IED) in the EEG increased (OR = 1.98) and administration of ASM decreased (OR = 0.43) recurrence rates significantly. CONCLUSIONS: The new definition of epilepsy was associated with increased application of ASM, but not with reduced recurrence rates. The study confirms the presence of IED as a strong risk factor for seizure recurrence and the protective effect of ASM. The influence of imaging findings, which have a strong impact on the new definition of epilepsy, could not be confirmed.

Morphometric correlates in patients with functional seizures with and without comorbid epilepsy.

OBJECTIVE: Functional seizures (FS) or psychogenic, non-epileptic seizures (PNES) are episodic alterations of behaviour with similar semiology to epileptic seizures but which are not caused by epileptic brain activity. Epilepsy patients show a high risk in developing FS; therefore, the purpose of this study is to examine morphometric correlates in patients with FS as well as in epilepsy patients with FS by comparing them separately to healthy controls (HC). METHODS: Twenty-one clinical three-dimensional (3D) T1-magnetic resonance imaging (MRI) scans of patients with FS (FS group) and 15 patients with FS and epilepsy (EFS group) were retrospectively compared with one control group of 21 age- and gender-matched HC. Two separate general linear model analyses were conducted via FreeSurfer version 6.0. RESULTS: The study population consisted of 21 FS patients (66.7% females, n = 14) with a median age at the time of the scan of 24 years (range 17-44 years); 15 EFS patients (80% females, n = 12) with a median age at the time of the scan of 27 years (range 16-43 years); and 21 healthy subjects (66.7% females, n = 14) with a median age at the time of the scan of 24 years (range 19-38 years). Both patient groups showed an increased Cth in the right prefrontal lobe: in the FS group in the right superior frontal, rostral middle frontal gyri and the right orbitofrontal cortex and, in the EFS group, in the right superior frontal gyrus and the right orbitofrontal cortex. Decreases in Cth were present in the right lateral occipital lobe in the FS group, while also in both hemispheres in the EFS group, namely the left paracentral, superior frontal, caudal middle frontal, lateral occipital and right superior frontal gyri. Neither group showed changes in curvature. CONCLUSION: These results suggest alterations in regions of emotional processing and executive control in patients with FS regardless of the presence of epilepsy.

Diffusion magnetic resonance imaging connectome features are predictive of functional lateralization of semantic processing in the anterior temporal lobes.

Assessment of regional language lateralization is crucial in many scenarios, but not all populations are suited for its evaluation via task-functional magnetic resonance imaging (fMRI). In this study, the utility of structural connectome features for the classification of language lateralization in the anterior temporal lobes (ATLs) was investigated. Laterality indices for semantic processing in the ATL were computed from task-fMRI in 1038 subjects from the Human Connectome Project who were labeled as stronger rightward lateralized (RL) or stronger leftward to bilaterally lateralized (LL) in a data-driven approach. Data of unrelated subjects (n = 432) were used for further analyses. Structural connectomes were generated from diffusion-MRI tractography, and graph theoretical metrics (node degree, betweenness centrality) were computed. A neural network (NN) and a random forest (RF) classifier were trained on these metrics to classify subjects as RL or LL. After classification, comparisons of network measures were conducted via permutation testing. Degree-based classifiers produced significant above-chance predictions both during cross-validation (NN: AUC-ROC[CI] = 0.68[0.64-0.73], accuracy[CI] = 68.34%[63-73.2%]; RF: AUC-ROC[CI] = 0.7[0.66-0.73], accuracy[CI] = 64.81%[60.9-68.5]) and testing (NN: AUC-ROC[CI] = 0.69[0.53-0.84], accuracy[CI] = 68.09[53.2-80.9]; RF: AUC-ROC[CI] = 0.68[0.53-0.84], accuracy[CI] = 68.09[55.3-80.9]). Comparison of network metrics revealed small effects of increased node degree within the right posterior middle temporal gyrus (pMTG) in subjects with RL, while degree was decreased in the right posterior cingulate cortex (PCC). Above-chance predictions of functional language lateralization in the ATL are possible based on diffusion-MRI connectomes alone. Increased degree within the right pMTG as a right-sided homologue of a known semantic hub, and decreased hubness of the right PCC may form a structural basis for rightward-lateralized semantic processing.

Psychophysiological interaction analysis for the detection of stimulus-specific networks in reflex epilepsy.

We report detailed functional MRI (fMRI) analyses in a patient with reflex seizures elicited by driving along a specific rural crossroad or by watching a video thereof. Semiology consisted of epigastric aura, followed by a sensory seizure of the left hand and sporadic automotor seizures. The right amygdala-region (rh-amygdala) was surgically and electroclinically confirmed as the epileptogenic zone. Presurgical task-fMRI was performed, during which videos of the driving along that specific crossroad (IC), of another crossroad (NC) or noise were presented. Independent component analysis was conducted, and one component was used to aid in selection of a seed region within the rh-amygdala for subsequent psychophysiological interaction analysis (PPI). Here, the following regions showed stronger connectivity with the rh-amygdala seed during the IC condition compared to NC: right > left visual cortex, bilateral insulae, and right secondary somatosensory cortex (S2), potentially explaining epigastric aura and left somatosensory seizure semiology. Contralateral analyses did not reproduce these results. Overall, the ictogenic stimulus elicited enhanced connectivity of the epileptogenic rh-amygdala with visual cortex and further regions of potential seizure spread (S2, insula) as a putative mechanism of ictogenesis. Our results highlight the potential of PPI in the analysis of stimulus-dependent networks in patients with reflex epilepsies to gain insight into seizure generation.

Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.

BACKGROUND AND OBJECTIVES: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants. METHODS: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes. RESULTS: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms. DISCUSSION: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

Gender differences in concerns about planning to have children and child-rearing among patients with epilepsy: A prospective, multicenter study with 477 patients from Germany.

OBJECTIVE: To analyze the concerns and worries about planning to have children and being a parent as a person with epilepsy and investigate gender differences in these perceptions. METHODS: The Epi2020 study was a large multicenter study focusing on different healthcare aspects of adult patients with epilepsy in Germany. In addition to basic clinical and demographic characteristics, patients were asked to answer a questionnaire regarding their plan to have children, if they had children, and concerns about their children's health. Data were analyzed to detect differences between men and women with epilepsy according to age group. RESULTS: In total, 477 patients with epilepsy with a mean age of 40.5 years (SD = 15.5, range: 18-83 years) participated in this study; 280 (58.7%) were female and 197 (41.3%) were male. Both women and men frequently reported concerns and worries about having children: In the age group below 45 years of age, 72.5% of women and 58.2% of men described being worried to some extent that their children may also suffer from epilepsy (p = .006). Furthermore, 67.3% of women and 54.2% of men below the age of 45 years reported being worried that their children may be disabled (p = .003). Women were more likely to have family members who are reluctant to support their desire to have children (p = .048). CONCLUSION: Women with epilepsy of childbearing age are significantly more likely to report major concerns that their children might be disabled or also have epilepsy than men with epilepsy and, therefore, express more concerns about choosing to have a child. However, men also report frequent concerns and worries, and this should be addressed not only on request but should be included in the provision of general information on epilepsy.

First clinical postmarketing experiences in the treatment of epilepsies with brivaracetam: a retrospective observational multicentre study.

OBJECTIVES: Brivaracetam (BRV) is the latest approved antiepileptic drug and acts as a synaptic vesicle protein 2A ligand. The aim of the present study was to evaluate the efficacy and tolerability of BRV in the clinical setting. DESIGN: Retrospective, observational multicentre study. SETTING: We retrospectively collected clinical data of patients who received BRV in 10 epilepsy centres using a questionnaire that was answered by the reporting neurologist. PARTICIPANTS: Data of 615 epilepsy patients treated with BRV were included in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Efficacy regarding seizure frequency and tolerability of BRV were evaluated. Descriptive statistics complemented by X2 contingency tests and effect sizes were performed. RESULTS: Overall, 44% of the patients had a decreased, 38% a stable and 18% an increased seizure frequency. 17% of patients achieved seizure freedom after initiation of BRV. The seizure frequency decreased in 63% of 19 patients with BRV monotherapy. 27% reported adverse effects, but only 10% of patients with monotherapy. Brivaracetam was significantly more often associated with decreased seizure frequency in levetiracetam (LEV) naïve patients (p=0.012), but BRV also led to a decreased seizure frequency in 42% of patients who had been treated with LEV before, including 17% of patients who were completely seizure free. Adverse effects under LEV improved in 62% and deteriorated in 2% of patients after the switch to BRV. At latest follow-up (mean±SD = 26.3±6.5 months), 68% were still on BRV. CONCLUSIONS: The present study shows that results of the phase III studies on BRV match data from real life clinical settings. Brivaracetam seems to be a useful alternative in patients who have suffered adverse effects while taking LEV.

Brivaracetam in the Treatment of Patients with Epilepsy-First Clinical Experiences.

OBJECTIVES: To assess first clinical experiences with brivaracetam (BRV) in the treatment of epilepsies. METHODS: Data on patients treated with BRV from February to December 2016 and with at least one clinical follow-up were collected from electronic patient records. Data on safety and efficacy were evaluated retrospectively. RESULTS: In total, 93 patients were analyzed; 12 (12.9%) received BRV in monotherapy. The mean duration to follow-up was 4.85 months (MD = 4 months; SD = 3.63). Fifty-seven patients had more than one seizure per month at baseline and had a follow-up of more than 4 weeks; the rate of ≥50% responders was 35.1% (n = 20) in this group, of which five (8.8%) patients were newly seizure-free. In 50.5% (47/93), patients were switched from levetiracetam (LEV) to BRV, of which 43 (46.2%) were switched immediately. Adverse events (AE) occurred in 39.8%, with 22.6% experiencing behavioral and 25.8% experiencing non-behavioral AE. LEV-related AE (LEV-AE) were significantly reduced by switching to BRV. The discontinuation of BRV was reported in 26/93 patients (28%); 10 of those were switched back to LEV with an observed reduction of AE in 70%. For clinical reasons, 12 patients received BRV in monotherapy, 75% were seizure-free, and previous LEV-AE improved in 6/9 patients. BRV-related AE occurred in 5/12 cases, and five patients discontinued BRV. CONCLUSION: BRV seems to be a safe, easy, and effective option in the treatment of patients with epilepsy, especially in the treatment of patients who have psychiatric comorbidities and might not be good candidates for LEV treatment. BRV broadens the therapeutic spectrum and facilitates personalized treatment.