Fetal Assessment in Pregnancy (Indication and Methodology for Fetal Monitoring in a low-risk Population). Guideline of the DGGG, DEGUM, OEGGG and SGGG (S3-Level, AWMF Registry No. 015/089, February 2023). / Fetale Überwachung in der Schwangerschaft (Indikation und Methodik zur fetalen Zustandsdiagnostik im Low-Risk-Kollektiv). Leitlinie der DGGG, DEGUM, OEGGG und SGGG (S3-Level, AWMF-Registernummer 015/089, Februar 2023).

PURPOSE: The aim of this guideline was to find evidence on whether carrying out Doppler examinations and CTGs in low-risk cohorts of pregnant women improves outcomes. METHODS: First, a systematic search for guidelines was carried out. Identified guidelines were evaluated using the DELPHI instrument of the AWMF. Three guidelines were found to be suitable to evaluate CTG. Two DEGUM best practice guidelines were judged suitable to describe the methods. All studies on this issue were additionally analyzed using 8 PICO questions. A structured consensus of the participating professional societies was achieved using a nominal group process and a structured consensus conference moderated by an independent moderator. RECOMMENDATIONS: No antepartum Doppler sonography examinations should be carried out in low-risk cohorts in the context of antenatal care. No antepartum CTG should be carried out in low-risk cohorts. NOTE: The guideline will be published simultaneously in the official journals of both professional societies (i. e., Geburtshilfe und Frauenheilkunde for the DGGG and Ultraschall in der Medizin/European Journal of Ultrasound for the DEGUM).

The Long-Term Use of Diagnostic Subdural Electroencephalogram Electrodes and Subdural Hematoma: A Prospective Cohort Study.

OBJECTIVES: Seizures and status epilepticus (SE) are frequent complications of acute subdural hematoma (aSDH) associated with increased morbidity and mortality. Therefore, we aimed to evaluate whether invasive subdural electroencephalogram recording leads to earlier seizure detection and treatment initiation in patients with aSDH. DESIGN: Prospective, single-center, cohort trial. SETTING: Neurologic and neurosurgical ICUs of one academic hospital in Germany. PATIENTS: Patients with aSDH undergoing surgical treatment. In total, 76 patients were enrolled in this study, 31 patients (40.8%) were assigned to the invasive electroencephalogram (iEEG) monitoring group and 45 patients (59.2%) to control group. INTERVENTIONS: The electrode group was implanted with a subdural strip electrode providing up to 7 days of real-time electroencephalogram recording in the neurointensive care unit, whereas the control group received regular normal surface electroencephalograms during the 7-day period. The primary outcomes were the prevalence and time to seizures and SE occurrence. Secondary outcomes included neurologic outcomes assessed using the Glasgow Outcome Scale (GOS) at discharge and 6-month follow-up and the prevalence of focal structural epilepsy within 2 years after discharge. MEASUREMENTS AND MAIN RESULTS: The trial was stopped after a study committee meeting when the prespecified criteria were met. The iEEG and control groups were well-matched for clinical characteristics at admission. Frequencies of seizures and SE detection were significantly higher in the iEEG group than in the control group (61% vs 15.6%; p < 0.001 and 38.7% vs 11.1%; p = 0.005). Time to seizure and SE detection was significantly earlier (median 29.2 vs 83.8 hr; p = 0.018 and 17.2 vs 83.8 hr; p = 0.033) in the iEEG group than in the control group. Favorable outcomes (GOS 4-5) were more frequently achieved in the iEEG group than in the control group (58% vs 31%; p = 0.065). No significant differences were detected in long-term mortality or post-traumatic epilepsy. CONCLUSIONS: Invasive subdural electroencephalogram monitoring is valuable and safe for early seizure/SE detection and treatment and might improve outcomes in the neurocritical care of patients with aSDH.

Birth during off-hours: Impact of time of birth, staff´s seniority, and unit volume on maternal adverse outcomes-a population-based cross-sectional study of 87 065 deliveries.

BACKGROUND: The aim of this study was to investigate whether time of birth, unit volume, and staff seniority impact the incidence of maternal complications in deliveries ≥34 + 0 gestational weeks. METHODS: We conducted a population-based cross-sectional study of 87 065 deliveries occurring between 2004 and 2015 in ten public hospitals in Styria, Austria. A composite adverse maternal outcome measure of uterine atony, postpartum hysterectomy, postpartum bleeding, impaired wound healing, postpartum infections requiring antibiotic treatment, sepsis, or maternal death was used to compare outcomes by time of birth, unit volume, and staff seniority. Based on delivery data, generalized estimating equations (GEEs) were used to calculate the risk of maternal adverse outcomes. RESULTS: Maternal adverse events occurred in 1.33% of deliveries. Incidence of maternal adverse events was highest for units with >1000 deliveries (adjusted OR 1.40; CI 95%: 1.16-1.69) and higher for perinatal centers (adjusted OR 1.35; CI 95%: 1.15-1.57) compared with reference units (500-1000 deliveries/year). Delivery during the daytime compared with the afternoon and nighttime did not affect the incidence of maternal complications (P = 0.765 and P = 0.136, respectively). Compared with resident-guided deliveries, the odds ratio for an adverse event was the same when a consultant attended the delivery (adjusted OR 1.13; CI 95%: 0.98-1.30) but lower in deliveries managed by midwives only (adjusted OR 0.21; CI 95%: 0.07-0.64). CONCLUSION: Procedures performed during the night shift were not associated with increased complication rates. Delivery volume and high-volume centers were associated with the highest risk of maternal complications, and units with 500-1000 deliveries per year were the lowest. With increasing odds of pregnancy risks, these results change, and delivering in a high-volume center becomes at least as safe as delivering in a smaller unit.

Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies.

OBJECTIVE: The term 'precision medicine' describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy. METHODS: A systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management. RESULTS: We included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19%), and this was tried in 33/56 (59%) and was successful (ie, >50% seizure reduction) in 10/33 (30%) patients. In 73/293 (25%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33%). SIGNIFICANCE: Our survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach.

Postoperative outcomes and surgical ratio at a newly established epilepsy center: The first 100 procedures.

PURPOSE: To describe the patients' characteristics, surgical ratio, and outcomes following epilepsy surgery at the newly established Epilepsy Center Frankfurt Rhine-Main. METHODS: We retrospectively studied the first 100 consecutive patients, including adult (n = 77) and pediatric (n = 23) patients, with drug-resistant epilepsy who underwent resective or ablative surgical procedures at a single, newly established epilepsy center. Patient characteristics, seizure and neuropsychological outcomes, histopathology, complications, and surgical ratio were analyzed. RESULTS: The mean patient age was 28.8 years (children 10.6 years, adults 34.2 years). The mean epilepsy duration was 11.9 years (children 3.9 years, adults 14.3 years), and the mean follow-up was 1.5 years. At the most recent visit, 64% of patients remained completely seizure free [Engel IA]. The rates of perioperative complications and unexpected new neurological deficits were 5%, each. The proportion of patients showing deficits in one or more cognitive domains increased six months after surgery and decreased to presurgical proportions after two years. Symptoms of depression were significantly decreased and quality of life was significantly increased after surgery. The surgical ratio was 25.3%. CONCLUSION: Similar postsurgical outcomes were achieved at a newly established epilepsy center compared with long-standing epilepsy centers. The lower time to surgery may reflect a general decrease in time to surgery over the last decade or the improved accessibility of a new epilepsy center in a previously underserved area. The surgical ratio was not lower than reported for established centers.

Detection of cortical malformations using enhanced synthetic contrast images derived from quantitative T1 maps.

The detection of cortical malformations in conventional MR images can be challenging. Prominent examples are focal cortical dysplasias (FCD), the most common cause of drug-resistant focal epilepsy. The two main MRI hallmarks of cortical malformations are increased cortical thickness and blurring of the gray (GM) and white matter (WM) junction. The purpose of this study was to derive synthetic anatomies from quantitative T1 maps for the improved display of the above imaging characteristics in individual patients. On the basis of a T1 map, a mask comprising pixels with T1 values characteristic for GM is created from which the local cortical extent (CE) is determined. The local smoothness (SM) of the GM-WM junctions is derived from the T1 gradient. For display of cortical malformations, the resulting CE and SM maps serve to enhance local intensities in synthetic double inversion recovery (DIR) images calculated from the T1 map. The resulting CE- and/or SM-enhanced DIR images appear hyperintense at the site of cortical malformations, thus facilitating FCD detection in epilepsy patients. However, false positives may arise in areas with naturally elevated CE and/or SM, such as large GM structures and perivascular spaces. In summary, the proposed method facilitates the detection of cortical abnormalities such as cortical thickening and blurring of the GM-WM junction which are typical FCD markers. Still, subject motion artifacts, perivascular spaces, and large normal GM structures may also yield signal hyperintensity in the enhanced synthetic DIR images, requiring careful comparison with clinical MR images by an experienced neuroradiologist to exclude false positives.

The role of mTOR inhibitors in preventing epileptogenesis in patients with TSC: Current evidence and future perspectives.

Tuberous sclerosis complex (TSC) is one of the most common genetic causes of epilepsy. Mutations in the TSC1 or TSC2 genes lead to the dysregulation of the mechanistic target of rapamycin (mTOR) pathway. This mTOR pathway hyperactivation is associated with several processes resulting in epileptic conditions. The occurrence of seizures and their treatment outcomes seem to play a crucial role in cognitive and behavioral developments in patients with TSC. Mechanistic target of rapamycin inhibitors have been proven to be effective in epilepsy treatment in individuals with TSC. Specifically, because of their disease-modifying mechanism of action, they have the capability to prevent epileptogenesis in patients with TSC. This article will provide an overview of the current evidence of and delineate future perspectives for mTOR inhibitors and their role in preventing epileptogenesis.

Noncompliance of patients with driving restrictions due to uncontrolled epilepsy.

Epilepsies are a common and chronic neurological disorder characterized by sustained risk of recurrent seizures. Because of paroxysmal and often unpredictable occurrence of seizures, patients with uncontrolled epilepsy are subject to disease-specific restrictions in daily life, such as their career choice or specific work limitations. According to German law and many other European and international guidelines, driving is strictly prohibited in patients with uncontrolled epilepsy so as to increase active and passive safety in public road traffic. Nevertheless, a significant percentage of patients probably do not comply with these legal restrictions and drive on a regular basis. For this study, we analyzed a representative German cohort with 302 patients (mean age: 45.0 years ±â€¯16.4; 48% male) with established epilepsy to identify the number of patients driving without permission. Overall, 58.6% (n = 177) of patients had a driving license, 71.1% (n = 69/97) of patients were in seizure remission, and 52.7% (n = 108/205) of patients had uncontrolled epilepsy. Among patients in seizure remission, 54.6% (n = 53/97) reported regular driving while, among patients with uncontrolled epilepsy, 15.1% (n = 31/205) reported driving on a regular basis. No patient in the cohort stated driving without a valid license. Permanent employment, freelance work, the absence of a relevant disability, and living alone were identified as significant risk factors, which underlines the already existing evidence for the importance of a possible restricted access to the labor market as motive for disregarding legal driving restrictions. In our opinion, specialized and generally available social counseling with a special focus on vocational and career guidance is urgently needed to improve compliance with epilepsy-caused driving restrictions and the underlying reasons for violating these rules. In addition, more effort has to be spent on improving diagnostics and treatment of epilepsy to reduce the number of patients with uncontrolled seizures. Comprehensive introduction of self-driving vehicles may also help to improve mobility of patients with refractory epilepsy.

Invasive EEG-electrodes in presurgical evaluation of epilepsies: Systematic analysis of implantation-, video-EEG-monitoring- and explantation-related complications, and review of literature.

INTRODUCTION: Stereoelectroencephalography (sEEG) is a diagnostic procedure for patients with refractory focal epilepsies that is performed to localize and define the epileptogenic zone. In contrast to grid electrodes, sEEG electrodes are implanted using minimal invasive operation techniques without large craniotomies. Previous studies provided good evidence that sEEG implantation is a safe and effective procedure; however, complications in asymptomatic patients after explantation may be underreported. The aim of this analysis was to systematically analyze clinical and imaging data following implantation and explantation. RESULTS: We analyzed 18 consecutive patients (mean age: 30.5 years, range: 12-46; 61% female) undergoing invasive presurgical video-EEG monitoring via sEEG electrodes (n = 167 implanted electrodes) over a period of 2.5 years with robot-assisted implantation. There were no neurological deficits reported after implantation or explantation in any of the enrolled patients. Postimplantation imaging showed a minimal subclinical subarachnoid hemorrhage in one patient and further workup revealed a previously unknown factor VII deficiency. No injuries or status epilepticus occurred during video-EEG monitoring. In one patient, a seizure-related asymptomatic cross break of two fixation screws was found and led to revision surgery. Unspecific symptoms like headaches or low-grade fever were present in 10 of 18 (56%) patients during the first days of video-EEG monitoring and were transient. Postexplantation imaging showed asymptomatic and small bleedings close to four electrodes (2.8%). CONCLUSION: Overall, sEEG is a safe and well-tolerated procedure. Systematic imaging after implantation and explantation helps to identify clinically silent complications of sEEG. In the literature, complication rates of up to 4.4% in sEEG and in 49.9% of subdural EEG are reported; however, systematic imaging after explantation was not performed throughout the studies, which may have led to underreporting of associated complications.

Seizure management and prescription patterns of anticonvulsants in Dravet syndrome: A multicenter cohort study from Germany and review of literature.

OBJECTIVE: The aim of this study was to describe the treatment pattern of patients with Dravet syndrome (DS) in Germany with routine antiepileptic drugs (AEDs) and emergency medication, and to review the literature of real-world evidence on medicine utilization of patients with DS in Europe. METHODS: Patient use of routine AEDs and emergency medications over 3-6 months was analyzed from a 2018 multicenter survey of 93 caregivers of patients with DS throughout Germany. Results were contextualized in a review of real-world evidence on medicine utilization of patients with DS in Europe. RESULTS: The variety of medications and the most frequent combinations routinely used by patients with DS (AEDs and others) are described. Patients use a large number of pharmaceutical treatments to manage seizures. The five most commonly used AEDs were sodium valproate (66% of the patients; mean daily dose: 660 mg; 24.5 mg per kg bodyweight), bromide (44%; 1462 mg; 51.2 mg per kg), clobazam (41%; 10.4 mg; 0.32 mg per kg), stiripentol (35%; 797 mg; 27.6 mg per kg), and topiramate (24%; 107 mg; 3.5 mg per kg). Ninety percent had reported using emergency medications in the last 3 months;, with the most common medications being Buccolam (40%, an oromucosal form of midazolam) and diazepam (20%, mostly rectal application). No discernable relationships between current medication and age or seizure frequency were observed. SIGNIFICANCE: This is the first comprehensive report of routine AEDs and emergency medication use in a large sample of patients with DS in Germany over a period of 3-6 months and shows that despite the most common AED combinations being in line with clinical guidelines/best practice, there is no discernable impact of best treatment on seizure frequency. We find a higher use of bromide in Germany compared with other real-world evidence in Europe.

Use of brivaracetam in genetic generalized epilepsies and for acute, intravenous treatment of absence status epilepticus.

OBJECTIVE: The objective of this study was to evaluate effectiveness, retention, and tolerability of brivaracetam (BRV) in genetic generalized epilepsies (GGE) in clinical practice. METHODS: A multicenter, retrospective cohort study recruiting all patients that started BRV in 2016 and 2017. RESULTS: A total of 61 patients (mean age = 29.8, range = 9-90 years, 41 female [67%]) were treated with BRV. They were difficult to control, with 2.4 failed antiepileptic drugs (AEDs) in the past, taking 1.9 AEDs on average at baseline. The length of exposure to BRV ranged from 7 days to 24 months, with a mean retention time of 7.9 months, resulting in a total exposure time to BRV of 483 months. The retention rate was 82% at 3 months and 69% at 6 months. Efficacy at 3 months was 36% (50% responder rate), with 25% seizure-free for 3 months. Patients with juvenile myoclonic epilepsy showed a responder rate of 60%, with 40% being free of any seizures. Long-term 50% responder rate was present in 17 patients (28%; 11 seizure-free [18%]) for >6 months and in 14 patients (23%; 10 seizure-free [16%]) for >12 months. Treatment-emergent adverse events were observed in 26% of the patients, with the most common being somnolence, ataxia, and psychobehavioral adverse events. Use of intravenous BRV with bolus injection of 200-300 mg in two females with absence status epilepticus was well tolerated, but did not result in cessation of status epilepticus. SIGNIFICANCE: Use of BRV in GGE is well tolerated, and 50% responder rates are similar to those observed in the regulatory trials for focal epilepsies. An immediate switch from levetiracetam (LEV) to BRV at a ratio of 15:1 is feasible. The occurrence of psychobehavioral adverse events seems less prominent than under LEV, and a switch to BRV can be considered in patients with LEV-induced adverse events.

Prenatal acupuncture: Women's expectations and satisfaction and influence on labor.

BACKGROUND: Use of prenatal acupuncture for labor preparation is common, but there is still conflicting evidence with respect to its objective obstetric benefits. There is little information on women's expectations and subjective experiences with acupuncture treatments. METHODS: In this retrospective cohort study, a validated questionnaire on women's treatment satisfaction was sent to women who had received prenatal acupuncture at the obstetric clinic of the Medical University of Graz, Austria within the last 3 years. The electronic obstetric database was used to extract detailed clinical and obstetric data of women who received acupuncture and delivered at the hospital. For comparison, obstetric data were matched with a control group of women without prenatal acupuncture, who had given birth at the hospital during the study period. RESULTS: The questionnaire was sent to 150 women, out of which 70 (46.7%) completed and returned the questionnaire. Analysis of the questionnaire indicated good overall satisfaction (mean sum score 26.22 ± 4.72) with acupuncture treatment-97.1% indicated that they were very or quite satisfied. Responders did not differ from nonresponders, except for the time between delivery and questionnaire (P = .015). Comparisons between the deliveries after prenatal acupuncture (n = 144) and the matched control deliveries (n = 576) showed no statistical significant differences in the length of labor and use of analgesics. CONCLUSION: Prenatal acupuncture is likely to have positive effects on pregnant women, aside from an objective influence on labor duration and pain.

Postmarketing experience with brivaracetam in the treatment of epilepsies: A multicenter cohort study from Germany.

OBJECTIVE: To evaluate factors predicting efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice. METHODS: A multicenter, retrospective cohort study recruiting all patients who started BRV between February and November 2016 with observation time between 3 and 12 months. RESULTS: Of a total of 262 patients (mean age 40, range 5-81 years, 129 male) treated with BRV, 227 (87%) were diagnosed to have focal, 19 (7%) idiopathic generalized and 8 (3%) symptomatic generalized epilepsy, whereas 8 (3%) were unclassified. The length of exposure to BRV ranged from 1 day to 12 months, with a median retention time of 6.1 months, resulting in a total exposure time to BRV of 1,504 months. The retention rate was 79.4% at 3 months and 75.8% at 6 months. Efficacy at 3 months was 41.2% (50% responder rate) with 14.9% seizure-free for 3 months and, at 6 months, 40.5% with 15.3% seizure-free. Treatment-emergent adverse events were observed in 37.8% of the patients, with the most common being somnolence, dizziness, and behavioral adverse events (BAEs). BAE that presented under previous levetiracetam (LEV) treatment improved upon switch to BRV in 57.1% (20/35) and LEV-induced somnolence improved in 70.8% (17/24). Patients with BAE on LEV were more likely to develop BAE on BRV (odds ratio [OR] 3.48, 95% confidence interval [CI] 1.53-7.95). SIGNIFICANCE: BRV in broad clinical postmarketing use is a well-tolerated anticonvulsant drug with 50% responder rates, similar to those observed in the regulatory trials, even though 90% of the patients included had previously been exposed to LEV. An immediate switch from LEV to BRV at a ratio of 10:1 to 15:1 is feasible. The only independent significant predictor of efficacy was the start of BRV in patients not currently taking LEV. The occurrence of BAE during previous LEV exposure predicted poor psychobehavioral tolerability of BRV treatment. A switch to BRV can be considered in patients with LEV-induced BAE.

Treatment of refractory and super-refractory status epilepticus with brivaracetam: A cohort study from two German university hospitals.

PURPOSE: We aimed to ascertain the possible use of brivaracetam (BRV) as an option for treatment of status epilepticus (SE). METHODS: A review of medical records was carried out to detect BRV administration in SE patients treated in Frankfurt and Greifswald during the period February 2016 to January 2017. The primary outcome question concerned SE resolution after BRV initiation. RESULTS: During that period, BRV was started with eleven adult patients with SE. Five of these were female, and the median age was 64 (interquartile range [IQR] 21years). The median SE duration before BRV initiation was 5days (IQR 9days); the median number of previous anticonvulsants used was 4 (IQR 5). Initial BRV doses ranged between 50mg and 400mg (median 100mg), titrated to a daily dose of 100 to 400mg (median 200mg). There was a cessation of SE in the first 24h of BRV in three patients (27%). While taking BRV, no serious side effects were seen. CONCLUSION: Based on these cases and previous data from animal experiments, BRV may prove useful in SE treatment, and trials would be warranted to examine BRV's efficacy in treating SE and how this efficacy might be influenced by co-administration with levetiracetam.

Personalized translational epilepsy research - Novel approaches and future perspectives: Part II: Experimental and translational approaches.

Despite the availability of more than 15 new "antiepileptic drugs", the proportion of patients with pharmacoresistant epilepsy has remained constant at about 20-30%. Furthermore, no disease-modifying treatments shown to prevent the development of epilepsy following an initial precipitating brain injury or to reverse established epilepsy have been identified to date. This is likely in part due to the polyetiologic nature of epilepsy, which in turn requires personalized medicine approaches. Recent advances in imaging, pathology, genetics, and epigenetics have led to new pathophysiological concepts and the identification of monogenic causes of epilepsy. In the context of these advances, the First International Symposium on Personalized Translational Epilepsy Research (1st ISymPTER) was held in Frankfurt on September 8, 2016, to discuss novel approaches and future perspectives for personalized translational research. These included new developments and ideas in a range of experimental and clinical areas such as deep phenotyping, quantitative brain imaging, EEG/MEG-based analysis of network dysfunction, tissue-based translational studies, innate immunity mechanisms, microRNA as treatment targets, functional characterization of genetic variants in human cell models and rodent organotypic slice cultures, personalized treatment approaches for monogenic epilepsies, blood-brain barrier dysfunction, therapeutic focal tissue modification, computational modeling for target and biomarker identification, and cost analysis in (monogenic) disease and its treatment. This report on the meeting proceedings is aimed at stimulating much needed investments of time and resources in personalized translational epilepsy research. This Part II includes the experimental and translational approaches and a discussion of the future perspectives, while the diagnostic methods, EEG network analysis, biomarkers, and personalized treatment approaches were addressed in Part I [1].

Personalized translational epilepsy research - Novel approaches and future perspectives: Part I: Clinical and network analysis approaches.

Despite the availability of more than 15 new "antiepileptic drugs", the proportion of patients with pharmacoresistant epilepsy has remained constant at about 20-30%. Furthermore, no disease-modifying treatments shown to prevent the development of epilepsy following an initial precipitating brain injury or to reverse established epilepsy have been identified to date. This is likely in part due to the polyetiologic nature of epilepsy, which in turn requires personalized medicine approaches. Recent advances in imaging, pathology, genetics and epigenetics have led to new pathophysiological concepts and the identification of monogenic causes of epilepsy. In the context of these advances, the First International Symposium on Personalized Translational Epilepsy Research (1st ISymPTER) was held in Frankfurt on September 8, 2016, to discuss novel approaches and future perspectives for personalized translational research. These included new developments and ideas in a range of experimental and clinical areas such as deep phenotyping, quantitative brain imaging, EEG/MEG-based analysis of network dysfunction, tissue-based translational studies, innate immunity mechanisms, microRNA as treatment targets, functional characterization of genetic variants in human cell models and rodent organotypic slice cultures, personalized treatment approaches for monogenic epilepsies, blood-brain barrier dysfunction, therapeutic focal tissue modification, computational modeling for target and biomarker identification, and cost analysis in (monogenic) disease and its treatment. This report on the meeting proceedings is aimed at stimulating much needed investments of time and resources in personalized translational epilepsy research. Part I includes the clinical phenotyping and diagnostic methods, EEG network-analysis, biomarkers, and personalized treatment approaches. In Part II, experimental and translational approaches will be discussed (Bauer et al., 2017) [1].

Intranasal midazolam during presurgical epilepsy monitoring is well tolerated, delays seizure recurrence, and protects from generalized tonic-clonic seizures.

OBJECTIVE: To evaluate the tolerability and efficacy of the ictal and immediate postictal application of intranasal midazolam (in-MDZ) in adolescents and adults during video-electroencephalography (EEG) monitoring. METHODS: Medical records of all patients treated with in-MDZ between 2008 and 2014 were reviewed retrospectively. For each single patient, the time span until recurrence of seizures was analyzed after an index seizure with and without in-MDZ application. To prevent potential bias, we defined the first seizure with application of in-MDZ as the in-MDZ index seizure. The control index seizure was the preceding, alternatively the next successive seizure without application of in-MDZ. RESULTS: In total, 75 epilepsy patients (mean age 34 ± 14.7 years; 42 male, 33 female) were treated with in-MDZ (mean dose 5.1 mg). Adverse events were observed in four patients (5.3%), and no serious adverse events occurred. The median time after EEG seizure onset before administration of in-MDZ was 2.17 min (interquartile range [IQR] 03.82; range 0.13-15.0 min). Over the next 12 h after in-MDZ, the number of seizures was significantly lower (p = 0.031). The median seizure-free interval was significantly longer following treatment with in-MDZ (5.83 h; IQR 6.83, range 0.4-23.87) than it was for those with no in-MDZ treatment (2.37 h; IQR 4.87, range 0.03-21.87; p = 0.015). Conversely, the likelihood of the patient developing a subsequent seizure was four times higher (odds ratio [OR] 4.33, 95% confidence interval [CI] 1.30-14.47) in the first hour and decreased gradually after 12 h (OR 1.5, 95% CI 1.06-2.12). The occurrence of generalized tonic-clonic seizures was lower in the in-MDZ group in the 24-h observation period (OR 4.67, 95% CI 1.41-15.45; p = 0.009). SIGNIFICANCE: Ictal and immediate postictal administration of in-MDZ was well tolerated and not associated with serious adverse events. We demonstrated a significant reduction of subsequent seizures (all seizure types) for a 12 h period and of generalized tonic-clonic seizures for 24 h following in-MDZ.

Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy.

Partial deletions of the RBFOX1 gene encoding the neuronal splicing regulator have been reported in a range of neurodevelopmental diseases including idiopathic/genetic generalized epilepsy (IGE/GGE), childhood focal epilepsy, and self-limited childhood benign epilepsy with centrotemporal spikes (BECTS, rolandic epilepsy), and autism. The protein regulates alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. Herein, we examined whether structural deletions affecting RBFOX1 exons confer susceptibility to common forms of juvenile and adult focal epilepsy syndromes. We screened 807 unrelated patients with sporadic focal epilepsy, and we identified seven hemizygous exonic RBFOX1 deletions in patients with sporadic focal epilepsy (0.9%) in comparison to one deletion found in 1,502 controls. The phenotypes of the patients carrying RBFOX1 deletions comprise magnetic resonance imaging (MRI)-negative epilepsy of unknown etiology with frontal and temporal origin (n = 5) and two patients with temporal lobe epilepsy with hippocampal sclerosis. The epilepsies were largely pharmacoresistant but not associated with intellectual disability. Our study extends the phenotypic spectrum of RBFOX1 deletions as a risk factor for focal epilepsy and suggests that exonic RBFOX1 deletions are involved in the broad spectrum of focal and generalized epilepsies.

A common SCN1A splice-site polymorphism modifies the effect of carbamazepine on cortical excitability--a pharmacogenetic transcranial magnetic stimulation study.

OBJECTIVE: SCN1A encodes the alpha subunit of the voltage-gated sodium channel and plays a crucial role in several epilepsy syndromes. The common SCN1A splice-site polymorphism rs3812718 (IVS5N+5 G>A) might contribute to the pathophysiology underlying genetic generalized epilepsies and is associated with electrophysiologic properties of the channel and the effect of sodium-channel blocking antiepileptic drugs. We assessed the effects of the rs3812718 genotype on cortical excitability at baseline and after administration of carbamazepine in order to investigate the mechanism of this association. METHODS: Paired-pulse transcranial magnetic stimulation (TMS) was applied in 92 healthy volunteers with the homozygous genotypes AA or GG of rs3812718 at baseline and after application of 400 mg of carbamazepine or placebo in a double-blind, randomized, crossover design. Resting motor threshold (RMT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP) were determined. RESULTS: At baseline there was no significant difference in any TMS parameter. Genotype GG was associated with a higher carbamazepine-induced increase in CSP duration as compared to AA (multivariate analysis of covariance [MANCOVA], p = 0.013). An expected significant increase in RMT was genotype independent. SIGNIFICANCE: We found that the rs3812718 genotype modifies the effect of carbamazepine on CSP duration (mainly reflecting modulation of γ-aminobutyric acid (GABA)ergic inhibition), but not on RMT (mainly reflecting modulation of voltage-gated sodium channels). This provides evidence that rs3812718 affects the pharmacoresponse to carbamazepine via an effect on GABAergic cortical interneurons. Our results also confirm that TMS is useful to investigate the effect of genetic variants on cortical excitability and pharmacoresponse.