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Epilepsy is one of the most prevalent neurological disorders, affecting more than 45 million people worldwide. Recent advances in genetic techniques, such as next-generation sequencing, have driven genetic discovery and increased our understanding of the molecular and cellular mechanisms behind many epilepsy syndromes. These insights prompt the development of personalized therapies tailored to the genetic characteristics of an individual patient. However, the surging number of novel genetic variants renders the interpretation of pathogenetic consequences and of potential therapeutic implications ever more challenging. Model organisms can help explore these aspects in vivo . In the last decades, rodent models have significantly contributed to our understanding of genetic epilepsies but their establishment is laborious, expensive, and time-consuming. Additional model organisms to investigate disease variants on a large scale would be desirable. The fruit fly Drosophila melanogaster has been used as a model organism in epilepsy research since the discovery of “bang-sensitive” mutants more than half a century ago. These flies respond to mechanical stimulation, such as a brief vortex, with stereotypic seizures and paralysis. Furthermore, the identification of seizure-suppressor mutations allows to pinpoint novel therapeutic targets. Gene editing techniques, such as CRISPR/Cas9, are a convenient way to generate flies carrying disease-associated variants. These flies can be screened for phenotypic and behavioral abnormalities, shifting of seizure thresholds, and response to anti-seizure medications and other substances. Moreover, modification of neuronal activity and seizure induction can be achieved using optogenetic tools. In combination with calcium and fluorescent imaging, functional alterations caused by mutations in epilepsy genes can be traced. Here, we review Drosophila as a versatile model organism to study genetic epilepsies, especially as 81% of human epilepsy genes have an orthologous gene in Drosophila . Furthermore, we discuss newly established analysis techniques that might be used to further unravel the pathophysiological aspects of genetic epilepsies.

Bilateral cyclic high frequency deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) reduces the seizure count in a subset of patients with epilepsy. Detecting stimulation-induced alterations of pathological brain networks may help to unravel the underlying physiological mechanisms related to effective stimulation delivery and optimize target engagement. We acquired 64-channel electroencephalography during ten ANT-DBS cycles (145 ​Hz, 90 ​μs, 3–5 ​V) of 1-min ON followed by 5-min OFF stimulation to detect changes in cortical activity related to seizure reduction. The study included 14 subjects (three responders, four non-responders, and seven healthy controls). Mixed-model ANOVA tests were used to compare differences in cortical activity between subgroups both ON and OFF stimulation, while investigating frequency-specific effects for the seizure onset zones. ANT-DBS had a widespread desynchronization effect on cortical theta and alpha band activity in responders, but not in non-responders. Time domain analysis showed that the stimulation induced reduction in theta-band activity was temporally linked to the stimulation period. Moreover, stimulation induced theta-band desynchronization in the temporal lobe channels correlated significantly with the therapeutic response. Responders to ANT-DBS and healthy-controls had an overall lower level of theta-band activity compared to non-responders. This study demonstrated that temporal lobe channel theta-band desynchronization may be a predictive physiological hallmark of therapeutic response to ANT-DBS and may be used to improve the functional precision of this intervention by verifying implantation sites, calibrating stimulation contacts, and possibly identifying treatment responders prior to implantation. •ANT-DBS reduces theta and alpha activity in the temporal lobe of therapy responders.•Theta activity levels in the temporal lobes correlate with seizure reduction rates.•Non-responders show elevated theta activity levels compared to healthy controls.•This biomarker may support effective stimulation and optimize target engagement.

Most of our knowledge on human CNS circuitry and related disorders originates from model organisms. How well such data translate to the human CNS remains largely to be determined. Human brain slice cultures derived from neurosurgical resections may offer novel avenues to approach this translational gap. We now demonstrate robust preservation of the complex neuronal cytoarchitecture and electrophysiological properties of human pyramidal neurons in long-term brain slice cultures. Further experiments delineate the optimal conditions for efficient viral transduction of cultures, enabling ‘high throughput’ fluorescence-mediated 3D reconstruction of genetically targeted neurons at comparable quality to state-of-the-art biocytin fillings, and demonstrate feasibility of long term live cell imaging of human cells in vitro. This model system has implications toward a broad spectrum of translational studies, regarding the validation of data obtained in non-human model systems, for therapeutic screening and genetic dissection of human CNS circuitry.

Epilepsy affects over 50 million individuals worldwide, a significant proportion of whom are women with epilepsy (WWE) of childbearing age. This population faces unique challenges related to hormonal fluctuations, e.g., during life stages such as breastfeeding or menopause. Antiseizure medications (ASMs) further complicate reproductive health by influencing menstrual function, contraception, pregnancy outcomes, bone health, and menopausal transition due to their teratogenic potential and hormonal interactive effects. Consequently, treatment strategies for WWE must consider these interactions and the risks associated with ASMs during pregnancy. This review aims to consolidate current data and guidelines for managing WWE throughout their reproductive years. These findings emphasize the importance of preconception counseling to optimize ASM regimens, ensuring both maternal well-being and fetal safety. Key recommendations from major international pregnancy registries are summarized to guide clinicians in selecting ASMs that minimize the risk of congenital malformations while maintaining effective seizure control. Additionally, this review explores the role of folic acid supplementation in preventing neural tube defects and outlines contraceptive options tailored for WWE. In conclusion, comprehensive education on the implications of epilepsy for reproductive health is crucial for WWE. By fostering informed decision-making through personalized counseling and careful medication management before, during, and after pregnancy, healthcare providers can significantly improve outcomes for both mothers and their children.

Background Deficits in gait and balance are common among neurological inpatients. Currently, assessment of these patients is mainly subjective. New assessment options using wearables may provide complementary and more objective information. Methods In this prospective cross-sectional feasibility study performed over a four-month period, all patients referred to a normal neurology ward of a university hospital and aged between 40 and 89 years were asked to participate. Gait and balance deficits were assessed with wearables at the ankles and the lower back. Frailty, sarcopenia, Parkinsonism, depression, quality of life, fall history, fear of falling, physical activity, and cognition were evaluated with questionnaires and surveys. Results Eighty-two percent ( n  = 384) of all eligible patients participated. Of those, 39% ( n  = 151) had no gait and balance deficit, 21% ( n  = 79) had gait deficits, 11% ( n  = 44) had balance deficits and 29% ( n  = 110) had gait and balance deficits. Parkinson’s disease, stroke, epilepsy, pain syndromes, and multiple sclerosis were the most common diseases. The assessment was well accepted. Conclusions Our study suggests that the use of wearables for the assessment of gait and balance features in a clinical setting is feasible. Moreover, preliminary results confirm previous epidemiological data about gait and balance deficits among neurological inpatients. Evaluation of neurological inpatients with novel wearable technology opens new opportunities for the assessment of predictive, progression and treatment response markers.

Paroxysmal dyskinesias are episodic movement disorders that can be inherited or are sporadic in nature. The pathophysiology underlying these disorders remains largely unknown but may involve disrupted ion homeostasis due to defects in cell-surface channels or nutrient transporters. In this study, we describe a family with paroxysmal exertion-induced dyskinesia (PED) over 3 generations. Their PED was accompanied by epilepsy, mild developmental delay, reduced CSF glucose levels, hemolytic anemia with echinocytosis, and altered erythrocyte ion concentrations. Using a candidate gene approach, we identified a causative deletion of 4 highly conserved amino acids (Q282_S285del) in the pore region of the glucose transporter 1 (GLUT1). Functional studies in Xenopus oocytes and human erythrocytes revealed that this mutation decreased glucose transport and caused a cation leak that alters intracellular concentrations of sodium, potassium, and calcium. We screened 4 additional families, in which PED is combined with epilepsy, developmental delay, or migraine, but not with hemolysis or echinocytosis, and identified 2 additional GLUT1 mutations (A275T, G314S) that decreased glucose transport but did not affect cation permeability. Combining these data with brain imaging studies, we propose that the dyskinesias result from an exertion-induced energy deficit that may cause episodic dysfunction of the basal ganglia, and that the hemolysis with echinocytosis may result from alterations in intracellular electrolytes caused by a cation leak through mutant GLUT1.

IntroductionA novel focal cortex stimulation (FCS) device has recently received approval in Europe for patients with focal drug-resistant epilepsy (DRE). After 6 months of stimulation, 17 of 32 patients achieved ≥50% reduction in seizure frequency compared with their prestimulation baseline (responders). Currently, there is no established method for predicting FCS treatment response prior to implantation.Methods and analysisThis is an ongoing combined retrospective-prospective non-interventional multicentre study. Clinical data of up to 100 patients treated with FCS are collected across 20 collaborating epilepsy centres in four European countries. The key outcome parameters, seizure frequency and severity, are measured along with metrics on cognition, mood and quality of life, both pre-electrode and postelectrode implantation. The data are complemented by demographics, medical history and information on antiseizure medication and FCS treatment parameters during the stimulation period. In addition to clinical data, MRI and electroencephalography registrations are used to gain insights into spatial and electrophysiological aspects of FCS. Multivariate statistical and machine learning analyses are employed to identify key predictive biomarkers associated with patient outcomes (responders vs non-responders). The primary goal is to improve counselling for DRE patients by identifying promising candidates for FCS treatment.Ethics and disseminationThis study has received approval from the ethics committee of the University of Freiburg, Germany (23–1540 S1; 23–1183_1-S1-retro). The same approval is applicable for all participating centres in Germany as part of a multicentre study. Ghent University Hospital, Belgium, has received approval for participation in the retrospective arm from their local ethics committee (ONZ-2024-0168). The final approvals for the participating Swiss and Austrian sites are still pending. The results will be made available to the public through peer-reviewed journals and conference presentations.

Mutations in SLC2A1 , encoding the glucose transporter type 1 (Glut1), cause a wide range of neurological disorders: (1) classical Glut1 deficiency syndrome (Glut1-DS) with an early onset epileptic encephalopathy including a severe epilepsy, psychomotor delay, ataxia and microcephaly, (2) paroxysmal exercise-induced dyskinesia (PED) and (3) various forms of idiopathic/genetic generalized epilepsies such as different forms of absence epilepsies. Up to now, focal epilepsy was not associated with SLC2A1 mutations. Here, we describe four cases in which focal seizures present the main or at least initial category of seizures. Two patients suffered from a classical Glut1-DS, whereas two individuals presented with focal epilepsy related to PED. We identified three novel SLC2A1 mutations in these unrelated individuals. Our study underscores that focal epilepsy can be caused by SLC2A1 mutations or that focal seizures may present the main type of seizures. Patients with focal epilepsy and PED should undergo genetic testing and can benefit from a ketogenic diet. But also individuals with pharmaco-resistant focal epilepsy and cognitive impairment might be candidates for genetic testing in SLC2A1 .

Discontinuing anti-seizure medication (ASM) should be considered in persons with epilepsy with long-term seizure freedom. Clinicians should also pursue ASM withdrawal in persons with one-time seizures without increased recurrence risk and those with suspected non-epileptic events. However, ASM withdrawal is associated with the risk of recurring seizures. Monitored ASM withdrawal in an epilepsy monitoring unit (EMU) could help better evaluate the risk of seizure recurrence. Here, we investigate the practice of EMU-guided ASM withdrawal, assess its indications, and aim to determine positive and negative predictors for successful withdrawal. We screened the medical records of all patients admitted to our EMU between November 1, 2019, and October 31, 2021, and included patients of at least 18 years admitted with the aim of permanent ASM withdrawal. We defined four groups of withdrawal indications: (1) long-term seizure freedom; (2) suspected non-epileptic events; (3) history of epileptic seizures but not fulfilling diagnostic criteria of epilepsy; and (4) seizure-freedom after epilepsy surgery. Successful withdrawal was defined according to the following criteria: no recoding of (sub)clinical seizure activity during VEM (groups 1, 2, and 3), patients did not meet the International League Against Epilepsy (ILAE) definition of epilepsy (groups 2 and 3) [14], and patients were discharged without ongoing ASM treatment (all groups). We also evaluated the prediction model by Lamberink et al. (LPM) for the risk of seizure recurrence in groups 1 and 3. 55/651 (8.6%) patients fulfilled the inclusion criteria. Withdrawal indications were distributed as follows; group 1: 2/55 (3.6%); group 2: 44/55 (80%); group 3: 9/55 (16,4%); group 4: 0/55. Overall, ASM withdrawal was successful in 90.9%. The sensitivity of the LPM for a 2-year 50% relapse risk threshold was 75%, the specificity 33.3%; for a 5-year relapse risk respectively 12.5% and 33.3%, suggesting that the model is not suitable for risk assessment in patients with one-time seizures or acute-symptomatic seizures, who constituted most of the evaluated patients. Our study suggests that EMU-guided ASM withdrawal could be a helpful tool to support clinical decision-making and improve patient safety. Prospective, randomized trials should further evaluate this method in the future.

Recent studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). PRRT2 is a presynaptic protein which seems to play an important role in exocytosis and neurotransmitter release. PKD is the most common form of paroxysmal movement disorder characterized by recurrent brief involuntary hyperkinesias triggered by sudden movements. Here, we sequenced PRRT2 in 14 sporadic and 8 familial PKD and ICCA cases of Caucasian origin and identified three novel mutations (c.919C>T/p.Gln307*, c.388delG/p.Ala130Profs*46, c.884G>A/p.Arg295Gln) predicting two truncated proteins and one probably damaging point mutation. A review of all published cases is also included. PRRT2 mutations occur more frequently in familial forms of PRRT2-related syndromes (80–100 %) than in sporadic cases (33-46 %) suggesting further heterogeneity in the latter. PRRT2 mutations were rarely described in other forms of paroxysmal dyskinesias deviating from classical PKD, as we report here in one ICCA family without kinesigenic triggers. Mutations are exclusively found in two exons of the PRRT2 gene at a high rate across all syndromes and with one major mutation (c.649dupC) in a mutational hotspot of nine cytosines, which is responsible for 57 % of all cases in all phenotypes. We therefore propose that genetic analysis rapidly performed in early stages of the disease is highly cost-effective and can help to avoid further unnecessary diagnostic and therapeutic interventions.