Dissecting the Shared Genetic Architecture of Common Epilepsies With Cortical Brain Morphology.

Background and Objectives: Epilepsies are associated with differences in cortical thickness (TH) and surface area (SA). However, the mechanisms underlying these relationships remain elusive. We investigated the extent to which these phenotypes share genetic influences. Methods: We analyzed genome-wide association study data on common epilepsies (n = 69,995) and TH and SA (n = 32,877) using Gaussian mixture modeling MiXeR and conjunctional false discovery rate (conjFDR) analysis to quantify their shared genetic architecture and identify overlapping loci. We biologically interrogated the loci using a variety of resources and validated in independent samples. Results: The epilepsies (2.4 k-2.9 k variants) were more polygenic than both SA (1.8 k variants) and TH (1.3 k variants). Despite absent genome-wide genetic correlations, there was a substantial genetic overlap between SA and genetic generalized epilepsy (GGE) (1.1 k), all epilepsies (1.1 k), and juvenile myoclonic epilepsy (JME) (0.7 k), as well as between TH and GGE (0.8 k), all epilepsies (0.7 k), and JME (0.8 k), estimated with MiXeR. Furthermore, conjFDR analysis identified 15 GGE loci jointly associated with SA and 15 with TH, 3 loci shared between SA and childhood absence epilepsy, and 6 loci overlapping between SA and JME. 23 loci were novel for epilepsies and 11 for cortical morphology. We observed a high degree of sign concordance in the independent samples. Discussion: Our findings show extensive genetic overlap between generalized epilepsies and cortical morphology, indicating a complex genetic relationship with mixed-effect directions. The results suggest that shared genetic influences may contribute to cortical abnormalities in epilepsies.

Unraveling the shared genetics of common epilepsies and general cognitive ability.

Objective: Cognitive impairment is prevalent among individuals with epilepsy, and it is possible that genetic factors can underlie this relationship. Here, we investigated the potential shared genetic basis of common epilepsies and general cognitive ability (COG). Methods: We applied linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR) to analyze different aspects of genetic overlap between COG and epilepsies. We used the largest available genome-wide association study data on COG (n = 269,867) and common epilepsies (n = 27,559 cases, 42,436 controls), including the broad phenotypes 'all epilepsy', focal epilepsies and genetic generalized epilepsies (GGE), and as well as specific subtypes. We functionally annotated the identified loci using a variety of biological resources and validated the results in independent samples. Results: Using MiXeR, COG (11.2k variants) was estimated to be almost four times more polygenic than 'all epilepsy', GGE, juvenile myoclonic epilepsy (JME), and childhood absence epilepsy (CAE) (2.5k - 2.9k variants). The other epilepsy phenotypes were insufficiently powered for analysis. We show extensive genetic overlap between COG and epilepsies with significant negative genetic correlations (-0.23 to -0.04). COG was estimated to share 2.9k variants with both GGE and 'all epilepsy', and 2.3k variants with both JME and CAE. Using conjFDR, we identified 66 distinct loci shared between COG and epilepsies, including novel associations for GGE (27), 'all epilepsy' (5), JME (5) and CAE (5). The implicated genes were significantly expressed in multiple brain regions. The results were validated in independent samples (COG: p = 1.0 × 10-14; 'all epilepsy': p = 5.6 × 10-3). Significance: Our study demonstrates a substantial genetic basis shared between epilepsies and COG and identifies novel overlapping genomic loci. Enhancing our understanding of the relationship between epilepsies and COG may lead to the development of novel comorbidity-targeted epilepsy treatments.

Treating status epilepticus in adults. / Behandling av status epilepticus hos voksne.

This clinical review examines the treatment of status epilepticus, a condition in which epileptic seizures are prolonged and pose a significant risk of brain damage and death. International guidelines recommend the use of benzodiazepines as first-line treatment, and these should be administered promptly and in appropriate doses. Second-line treatment involves the use of high-dose anti-seizure medications to stop and prevent seizures. If seizure activity persists, general anaesthesia should be administered as soon as possible. All neurological hospital departments should have established and rehearsed protocols for treating status epilepticus.

Astrocytes as critical players of the fine balance between inhibition and excitation in the brain: spreading depolarization as a mechanism to curb epileptic activity.

Spreading depolarizations (SD) are slow waves of complete depolarization of brain tissue followed by neuronal silencing that may play a role in seizure termination. Even though SD was first discovered in the context of epilepsy research, the link between SD and epileptic activity remains understudied. Both seizures and SD share fundamental pathophysiological features, and recent evidence highlights the frequent occurrence of SD in experimental seizure models. Human data on co-occurring seizures and SD are limited but suggestive. This mini-review addresses possible roles of SD during epileptiform activity, shedding light on SD as a potential mechanism for terminating epileptiform activity. A common denominator for many forms of epilepsy is reactive astrogliosis, a process characterized by morphological and functional changes to astrocytes. Data suggest that SD mechanisms are potentially perturbed in reactive astrogliosis and we propose that this may affect seizure pathophysiology.

Biological rhythms and epilepsy treatment.

Approximately one-third of patients with epilepsy are drug-refractory, necessitating novel treatment approaches. Chronopharmacology, which adjusts pharmacological treatment to physiological variations in seizure susceptibility and drug responsiveness, offers a promising strategy to enhance efficacy and tolerance. This narrative review provides an overview of the biological foundations for rhythms in seizure activity, clinical implications of seizure patterns through case reports, and the potential of chronopharmacological strategies to improve treatment. Biological rhythms, including circadian and infradian rhythms, play an important role in epilepsy. Understanding seizure patterns may help individualize treatment decisions and optimize therapeutic outcomes. Altering drug concentrations based on seizure risk periods, adjusting administration times, and exploring hormone therapy are potential strategies. Large-scale randomized controlled trials are needed to evaluate the efficacy and safety of differential and intermittent treatment approaches. By tailoring treatment to individual seizure patterns and pharmacological properties, chronopharmacology offers a personalized approach to improve outcomes in patients with epilepsy.

Reliable evaluation of functional connectivity and graph theory measures in source-level EEG: How many electrodes are enough?

OBJECTIVE: Using EEG to characterise functional brain networks through graph theory has gained significant interest in clinical and basic research. However, the minimal requirements for reliable measures remain largely unaddressed. Here, we examined functional connectivity estimates and graph theory metrics obtained from EEG with varying electrode densities. METHODS: EEG was recorded with 128 electrodes in 33 participants. The high-density EEG data were subsequently subsampled into three sparser montages (64, 32, and 19 electrodes). Four inverse solutions, four measures of functional connectivity, and five graph theory metrics were tested. RESULTS: The correlation between the results obtained with 128-electrode and the subsampled montages decreased as a function of the number of electrodes. As a result of decreased electrode density, the network metrics became skewed: mean network strength and clustering coefficient were overestimated, while characteristic path length was underestimated. CONCLUSIONS: Several graph theory metrics were altered when electrode density was reduced. Our results suggest that, for optimal balance between resource demand and result precision, a minimum of 64 electrodes should be utilised when graph theory metrics are used to characterise functional brain networks in source-reconstructed EEG data. SIGNIFICANCE: Characterisation of functional brain networks derived from low-density EEG warrants careful consideration.

Sleep cycle-dependent vascular dynamics in male mice and the predicted effects on perivascular cerebrospinal fluid flow and solute transport.

Perivascular spaces are important highways for fluid and solute transport in the brain enabling efficient waste clearance during sleep. However, the underlying mechanisms augmenting perivascular flow in sleep are unknown. Using two-photon imaging of naturally sleeping male mice we demonstrate sleep cycle-dependent vascular dynamics of pial arteries and penetrating arterioles: slow, large-amplitude oscillations in NREM sleep, a vasodilation in REM sleep, and a vasoconstriction upon awakening at the end of a sleep cycle and microarousals in NREM and intermediate sleep. These vascular dynamics are mirrored by changes in the size of the perivascular spaces of the penetrating arterioles: slow fluctuations in NREM sleep, reduction in REM sleep and an enlargement upon awakening after REM sleep and during microarousals in NREM and intermediate sleep. By biomechanical modeling we demonstrate that these sleep cycle-dependent perivascular dynamics likely enhance fluid flow and solute transport in perivascular spaces to levels comparable to cardiac pulsation-driven oscillations.

Temporal lobe epilepsy. / Temporallappsepilepsi.

The temporal lobes are the part of the brain most likely to give rise to epileptic seizures. Seizures originating in the temporal lobes vary greatly in character; some may be so unusual that they are not even recognised as epileptic. For patients who have been diagnosed with hippocampal sclerosis and whose seizures cannot be controlled with drugs, epilepsy surgery may be a good treatment option. In this brief clinical review, we summarise the key features of epilepsy and highlight the importance of accurate and early diagnosis for achieving good clinical outcomes.

The potential role of DNA methylation as preventive treatment target of epileptogenesis.

Pharmacological therapy of epilepsy has so far been limited to symptomatic treatment aimed at neuronal targets, with the result of an unchanged high proportion of patients lacking seizure control. The dissection of the intricate pathological mechanisms that transform normal brain matter to a focus for epileptic seizures-the process of epileptogenesis-could yield targets for novel treatment strategies preventing the development or progression of epilepsy. While many pathological features of epileptogenesis have been identified, obvious shortcomings in drug development are now believed to be based on the lack of knowledge of molecular upstream mechanisms, such as DNA methylation (DNAm), and as well as a failure to recognize glial cell involvement in epileptogenesis. This article highlights the potential role of DNAm and related gene expression (GE) as a treatment target in epileptogenesis.

Prediction of Long-term Survival After Status Epilepticus Using the ACD Score.

Importance: Early prediction of long-term mortality in status epilepticus is important given the high fatality rate in the years after diagnosis. Objective: To improve prognostication of long-term mortality after status epilepticus diagnosis. Design, Settings, and Participants: This retrospective, multicenter, multinational cohort study analyzed adult patients who were diagnosed with and treated for status epilepticus at university hospitals in Odense, Denmark, between January 1, 2008, and December 31, 2017, as well as in Oslo, Norway; Marburg, Germany; and Frankfurt, Germany. They were aged 18 years or older and had first-time, nonanoxic status epilepticus. A new scoring system, called the ACD score, for predicting 2-year (long-term) mortality after hospital discharge for status epilepticus was developed in the Danish cohort and validated in the German and Norwegian cohorts. The ACD score represents age at onset, level of consciousness at admission, and duration of status epilepticus. Data analysis was performed between September 1, 2019, and March 31, 2020. Exposures: Long-term follow-up using data from national and local civil registries in Denmark, Norway, and Germany. Main Outcomes and Measures: The predefined end point was 2-year survival for all patients and for a subgroup of patients with status epilepticus causes that were not damaging or were less damaging to the brain. Neurological deficits before and after onset, demographic characteristics, etiological categories of status epilepticus, comorbidities, survival, time points, treatments, and prognostic scores for different measures were assessed. Results: A total of 261 patients (mean [SD] age, 67.2 [14.8] years; 132 women [50.6%]) were included, of whom 145 patients (mean [SD] age, 66.3 [15.0] years; 78 women [53.8%]) had status epilepticus causes that were not damaging or were less damaging to the brain. The validation cohort comprised patients from Norway (n = 139) and Germany (n = 906). At hospital discharge, 29.8% of patients (n = 64 of 215) had new moderate to severe neurological deficits compared with baseline. New neurological deficits were a major predictor of 2-year survival after hospital discharge (odds ratio, 5.1; 95% CI, 2.2-11.8); this association was independent of etiological category. Nonconvulsive status epilepticus in coma and duration of status epilepticus were associated with development of new neurological deficits, and a simple 3-factor score (ACD score) combining these 2 risk factors with age at onset was developed to estimate survival after status epilepticus diagnosis. The ACD score had a linear correlation with 2-year survival (Pearson r2 = 0.848), especially in the subset of patients with a low likelihood of brain damage. Conclusions and Relevance: This study found that age, long duration, and nonconvulsive type of status epilepticus in coma were associated with the development of new neurological deficits, which were predictors of long-term mortality. Accounting for risk factors for new neurological deficits using the ACD score is a reliable method of prediction of long-term outcome in patients with status epilepticus causes that were not damaging or were less damaging to the brain.

Episodic Memory Dysfunction and Effective Connectivity in Adult Patients With Newly Diagnosed Nonlesional Temporal Lobe Epilepsy.

OBJECTIVE: Epilepsy is associated with both changes in brain connectivity and memory function, usually studied in the chronic patients. The aim of this study was to explore the presence of connectivity alterations measured by EEG in the parietofrontal network in patients with temporal lobe epilepsy (TLE), and to examine episodic memory, at the time point of diagnosis. METHODS: The parietofrontal network of newly diagnosed patients with TLE (N = 21) was assessed through electroencephalography (EEG) effective connectivity and compared with that of matched controls (N = 21). Furthermore, we assessed phenomenological aspects of episodic memory in both groups. Association between effective connectivity and episodic memory were assessed through correlation. RESULTS: Patients with TLE displayed decreased episodic (p ≤ 0.001, t = -5.18) memory scores compared with controls at the time point of diagnosis. The patients showed a decreased right parietofrontal connectivity (p = 0.03, F = 4.94) compared with controls, and significantly weaker connectivity in their right compared with their left hemisphere (p = 0.008, t = -2.93). There were no significant associations between effective connectivity and episodic memory scores. CONCLUSIONS: We found changes in both memory function and connectivity at the time point of diagnosis, supporting the notion that TLE involves complex memory functions and brain networks beyond the seizure focus to strongly interconnected brain regions, already early in the disease course. Whether the observed connectivity changes can be interpreted as functionally important to the alterations in memory function, it remains speculative.

Astrocytic Ca2+ Signaling in Epilepsy.

Epilepsy is one of the most common neurological disorders - estimated to affect at least 65 million worldwide. Most of the epilepsy research has so far focused on how to dampen neuronal discharges and to explain how changes in intrinsic neuronal activity or network function cause seizures. As a result, pharmacological therapy has largely been limited to symptomatic treatment targeted at neurons. Given the expanding spectrum of functions ascribed to the non-neuronal constituents of the brain, in both physiological brain function and in brain disorders, it is natural to closely consider the roles of astrocytes in epilepsy. It is now widely accepted that astrocytes are key controllers of the composition of the extracellular fluids, and may directly interact with neurons by releasing gliotransmitters. A central tenet is that astrocytic intracellular Ca2+ signals promote release of such signaling substances, either through synaptic or non-synaptic mechanisms. Accruing evidence suggests that astrocytic Ca2+ signals play important roles in both seizures and epilepsy, and this review aims to highlight the current knowledge of the roles of this central astrocytic signaling mechanism in ictogenesis and epileptogenesis.

Seizure control after late introduction of anakinra in a patient with adult onset Rasmussen's encephalitis.

Neuroinflammation has been considered an important pathophysiological process involved in epileptogenesis and may provide possibilities for new treatment possibilities. We present the case of a 45-year-old female with drug resistant epilepsy and progressive right-sided cerebral hemiatrophy associated with adult onset Rasmussen's encephalitis. Over a period of 26 years, she was treated with 14 different antiseizure medications, intravenous immunoglobulins, glucocorticosteroids, underwent two operations with focal resection and subpial transections, and tried out trigeminal nerve stimulation. Extensive blood tests, including antibodies relevant for autoimmune encephalitis, and brain biopsy did not show any signs of neuroinflammation. Eventually, the patient received the interleukin-1 receptor antagonist, anakinra. Within 1-2 days after injection, seizure frequency decreased significantly, and, after one week, the seizures stopped completely. Anakinra treatment was continued for 2 months. Stopping medication led to a relapse of seizures after 2 weeks, with a frequency of up to 45 seizures per day. Reintroduction of anakinra led to rapid recovery. Treatment with anakinra was continued for 7 months. The treatment was discontinued in April 2020, and the patient has been completely seizure free since then. There have been no other changes in antiseizure medication.

COVID-19 and epilepsy. / Covid-19 og epilepsi.

Can COVID-19 cause epilepsy, or increase the tendency to seizures in those with epilepsy? Is it safe for persons with epilepsy to be vaccinated against COVID-19?

The organization of functional neurocognitive networks in focal epilepsy correlates with domain-specific cognitive performance.

Understanding and diagnosing cognitive impairment in epilepsy remains a prominent challenge. New etiological models suggest that cognitive difficulties might not be directly linked to seizure activity, but are rather a manifestation of a broader brain pathology. Consequently, treating seizures is not sufficient to alleviate cognitive symptoms, highlighting the need for novel diagnostic tools. Here, we investigated whether the organization of three intrinsic, resting-state functional connectivity networks was correlated with domain-specific cognitive test performance. Using individualized EEG source reconstruction and graph theory, we examined the association between network small worldness and cognitive test performance in 23 patients with focal epilepsy and 17 healthy controls, who underwent a series of standardized pencil-and-paper and digital cognitive tests. We observed that the specific networks robustly correlated with test performance in distinct cognitive domains. Specifically, correlations were evident between the default mode network and memory in patients, the central-executive network and executive functioning in controls, and the salience network and social cognition in both groups. Interestingly, the correlations were evident in both groups, but in different domains, suggesting an alteration in these functional neurocognitive networks in focal epilepsy. The present findings highlight the potential clinical relevance of functional brain network dysfunction in cognitive impairment.