Add-on treatment with cenobamate is already effective at low doses in refractory focal epilepsy: A prospective observational study.

OBJECTIVE: Cenobamate, a novel antiseizure medication with a dual mechanism of action, has been shown in pivotal trials to significantly improve seizure control in treatment-resistant focal epilepsy. We aimed to evaluate whether these promising results could be confirmed in a real-world setting with a follow-up period of up to 12 months. METHODS: Patients from a tertiary epilepsy center who received cenobamate add-on between June 2021 and October 2023 were followed up prospectively at 3, 6, and 12 months after treatment initiation for assessment of seizure outcomes and treatment-related adverse events. RESULTS: The clinical cohort included 112 adult patients with 30% nonlesional cases and a wide spectrum of epileptogenic lesions underlying refractory focal epilepsy. We observed a significant reduction in monthly seizure frequency of all seizure types already after 3 months of treatment at a median cenobamate dose of 100 mg/day. Forty-six percent of patients were responders with a ≥50% seizure reduction, 26% had a ≥75% seizure reduction, and 9% became seizure-free. Among the 74 patients with available follow-up of 12 months, the responder rates reached 55%, 35%, and 19% for ≥50%, ≥75%, and 100% seizure reduction, respectively. After 3 months of treatment, 38% of patients reported adverse effects, mainly (84%) mild to moderate in intensity. Adjustment of comedication allowed successful management of adverse effects in 32% of patients. At a group level, there was no correlation between the cenobamate daily dose and the incidence of adverse events. SIGNIFICANCE: We found a clinically relevant response to cenobamate already at a low daily dose of 100 mg also in a patient cohort with a higher degree of drug resistance than in pivotal trials. Our prospectively collected data provide real-world evidence for high efficacy and good tolerability of the drug, although no standardized treatment protocol or comparison with a control group was applied.

Technical note: preliminary surgical experience with a new implantable epicranial stimulation device for chronic focal cortex stimulation in drug-resistant epilepsy.

PURPOSE: This study is to report some preliminary surgical considerations and outcomes after the first implantations of a new and commercially available implantable epicranial stimulation device for focal epilepsy. METHODS: We retrospectively analyzed data from clinical notes. Outcome parameters were as follows: wound healing, surgery time, and adverse events. RESULTS: Five patients were included (17-52 y/o; 3 female). Epicranial systems were uneventfully implanted under neuronavigation guidance. Some minor adverse events occurred. Wound healing in primary intention was seen in all patients. Out of these surgeries, certain concepts were developed: Skin incisions had to be significantly larger than expected. S-shaped incisions appeared to be a good choice in typical locations behind the hairline. Preoperative discussions between neurologist and neurosurgeon are mandatory in order to allow for the optimal coverage of the epileptogenic zone with the electrode geometry. CONCLUSION: In this first small series, we were able to show safe implantation of this new epicranial stimulation device. The use of neuronavigation is strongly recommended. The procedure is simple but not trivial and ideally belongs in the hands of a neurosurgeon.

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.

Listening to anxiety in persons with epilepsy. Development of an integrative assessment model based on qualitative interviews.

OBJECTIVE: The differentiation and assessment of anxiety in persons with epilepsy is the subject of current research. There is no consensus on which forms of anxiety are epilepsy-specific, what pathological significance they have, and how they should be conceptually systematized. The aim of this study was to detect formal landmarks that organize and further distinguish the clinical multitude of epilepsy-related anxiety, thereby establishing a basis on which an integrative assessment of epilepsy-specific fears can be developed. METHOD: Twenty-six patients with epilepsy-related fears were recruited for qualitative interviews at the Epilepsy Center of Freiburg in Germany. Prevalent types of anxiety included both periictal and interictal anxiety. Patients reported how living with epilepsy is associated with anxiety and to what extent. After an open interview, semi-structured questions were asked concerning epilepsy-specific anxiety, referring to established concepts and items. The contents of the interviews relating to anxiety were transcribed. RESULTS: The reported fears associated with epilepsy reflect the individual "pathography" of each patient. The potentially anxiety-inducing events within this pathography include the first seizure(s), especially in cases involving the amygdalae; the process of diagnostic procedures; therapy, including side effects of antiseizure medication, surgery as a therapeutic option, or a difficult physician-patient relationship; and the further course of the disease, including the fear of disease progression with brain damage, cognitive deterioration, or professional and social disintegration. The integrative assessment model derived from the pathography of the interviewed patients thus reflects the dynamics and quality of epilepsy-specific fears, especially in relation to the healthcare system, without instantly pathologizing them. It highlights that anxiety, to a variable degree, is perceived as an adequate and comprehensible emotion and might be a problem long before the diagnosis is made in the case of ictal fear. Furthermore, anxiety symptoms may (re-)emerge, consolidate, modulate, diminish, or even aggravate during the course of the disease. The integrative assessment model maps crucial events inherent to the healthcare system that may become relevant as objects of prevention, intervention, and therapy. CONCLUSION: The integrative assessment model can serve as a heuristic framework from which an integrative self-report questionnaire of epilepsy-specific anxiety might be designed. On the one hand, this would help to better understand the interrelation between epilepsy and anxiety in terms of their temporal occurrence and interdependence scientifically. On the other hand, it would allow for the enhancement of individual preventive and therapeutic measures for affected patients.

Surgical management of uterine fibroids.

PURPOSE OF REVIEW: Fibroids are benign pelvic masses and constitute the most common gynaecological condition. They create a significant health and social burden to many women because of heavy menstrual bleeding and fibroid pressure symptoms. Many women will be faced with the dilemma of surgical management to improve their symptoms at some point of their reproductive age. The aim of this article is to identify current surgical management of fibroids describing the technical steps, advantages, disadvantages and risks of each method. RECENT FINDINGS: The surgical management of fibroids remains challenging, as the overall prevalence, the clinical experience and the patient awareness is increasing because of an upgrade in our sonographic and magnetic resonance diagnostic tools. Unfortunately not every patient is able to benefit from tailor-made surgery that holistically evaluates individual needs including fertility aspirations. SUMMARY: This article provides the most current synopsis of every available surgical modality for fibroid management. Large prospective multicentre cohort studies are needed to definitely determine the most suitable operation for any individual suffering with fibroids; and perhaps artificial intelligence may offer a valuable tool in the future data analysis.

Perioperative hormone treatment of endometriosis.

PURPOSE OF REVIEW: The use of hormonally suppressive medication to reduce levels of reproductive hormones around the time of surgery is widely used in the management of endometriosis. This review summarizes the current evidence concerning the perioperative use of hormonal treatment in the management of endometriosis. RECENT FINDINGS: European Society of Human Reproduction and Embryology (ESHRE) guidanceSurgical Outcomes and Complications of Laparoscopic Hysterectomy for Endometriosis: A Multicentre Cohort StudyPre and postsurgical medical therapy for endometriosis surgery. Cochrane 2020Postoperative hormonal treatment for prevention of endometrioma recurrence after ovarian cystectomy: a systematic review and network meta-analysis. BJOG 2021. SUMMARY: The literature highlights the importance of hormonal treatment for symptom relief, reduced surgical complications and postoperative benefits, including a reduction in pain, disease recurrence and improved pregnancy rates. The treatment of endometriosis can be broadly categorized into medical, commonly using hormonal suppression medications and surgical, in which endometriosis tissue is excised or ablated. This review aims to outline current management strategies and examines the relationship between the two treatment modalities.

The prevalence of mental ill-health in women during pregnancy and after childbirth during the Covid-19 pandemic: a systematic review and Meta-analysis.

BACKGROUND: This systematic review aims to explore the prevalence of the impact of the COVID-19, MERS, and SARS pandemics on the mental health of pregnant women. METHODS: All COVID-19, SARS and MERS studies that evaluated the mental health of pregnant women with/without gynaecological conditions that were reported in English between December 2000 - July 2021 were included. The search criteria were developed based upon the research question using PubMed, Science Direct, Ovid PsycINFO and EMBASE databases. A wide search criterion was used to ensure the inclusion of all pregnant women with existing gynaecological conditions. The Newcastle-Ottawa-Scale was used to assess the risk of bias for all included studies. Random effects model with restricted maximum-likelihood estimation method was applied for the meta-analysis and I-square statistic was used to evaluate heterogeneity across studies. The pooled prevalence rates of symptoms of anxiety, depression, PTSD, stress, and sleep disorders with 95% confidence interval (CI) were computed. RESULTS: This systematic review identified 217 studies which included 638,889 pregnant women or women who had just given birth. There were no studies reporting the mental health impact due to MERS and SARS. Results showed that women who were pregnant or had just given birth displayed various symptoms of poor mental health including those relating to depression (24.9%), anxiety (32.8%), stress (29.44%), Post Traumatic Stress Disorder (PTSD) (27.93%), and sleep disorders (24.38%) during the COVID-19 pandemic. DISCUSSION: It is important to note that studies included in this review used a range of outcome measures which does not allow for direct comparisons between findings. Most studies reported self-reported measure of symptoms without clinical diagnoses so conclusions can be made for symptom prevalence rather than of mental illness. The importance of managing mental health during pregnancy and after-delivery improves the quality of life and wellbeing of mothers hence developing an evidence-based approached as part of pandemic preparedness would improve mental health during challenging times. OTHER: The work presented in this manuscript was not funded by any specific grants. A study protocol was developed and published in PROSPERO (CRD42021235356) to explore several key objectives.

The treatment of endometriosis-associated infertility.

PURPOSE OF REVIEW: To review the recent evidence around the treatment of infertility in patients with endometriosis. RECENT FINDINGS: The management of endometriosis associated infertility remains challenging. There have been an increasing number of prospective observational studies highlighting the role of surgery to enhance assisted conception amongst those with deep rectovaginal endometriosis. Further validation studies confirm the role of the endometriosis fertility index in prediction of reproductive outcomes after surgery, and confirm that it can be employed in counselling patients prior to surgery on their likelihood of spontaneous conception. Further randomized trials are required to establish the role of surgically treating superficial and deep endometriosis and both spontaneous and assisted conception outcomes. SUMMARY: Endometriosis continues to present challenges in counselling patients with regards to their fertility prospects. This article reviews the recent research findings that may assist in the management of patients with endometriosis associated infertility.

Nonsurgical management of adenomyosis: an overview of current evidence.

PURPOSE OF REVIEW: Adenomyosis is a condition where endometrium-like tissue spreads within the myometrium. Although its prevalence in the general population is not exactly known, its clinical manifestations are well established and include pelvic pain, dysmenorrhea (painful periods), heavy menstrual bleeding and subfertility [1] . Adenomyosis often coexists with other gynaecological conditions, such as endometriosis or fibroids, and may cloud the clinical presentation [2] . The aim of this article is to review current noninterventional, nonsurgical management modalities and wherever possible offer information that allows women to make safe and informed choices regarding their treatment options. RECENT FINDINGS: Recent studies support that medical strategies, including the Mirena coil, Dienogest and GnRH antagonists, are efficient in improving adenomyosis-associated symptoms. High-quality evidence is scarce and is needed to properly counsel women with this condition. Future research should prioritize overall pain, menstrual bleeding, quality of life and live birth as primary outcomes and assess women with different grades of adenomyosis. SUMMARY: This review provides the most current evidence with regards to the nonsurgical management of adenomyosis. In light of the paucity and low quality of existing data, high-quality trials are needed to definitely determine the impact of conservative and medical treatment on the clinical management of adenomyosis.

Ultrasound Prediction of Segmental Bowel Resection in Women with Rectovaginal Endometriosis: A Single-Center Experience.

STUDY OBJECTIVE: To retrospectively evaluate the ability of routinely collected preoperative ultrasound data to predict bowel resection during surgery for rectovaginal endometriosis. DESIGN AND SETTING: Patients at the University College London Hospital who underwent surgery for rectovaginal endometriosis during a 6-year period were identified from the prospectively generated hospital (British Society for Gynaecological Endoscopy) database. Imaging data were collected and analyzed to determine associations with the requirement for bowel resection. PATIENTS: We evaluated 228 consecutive women undergoing bowel surgery (shave, disc resection, or segmental resection) for rectovaginal endometriosis. INTERVENTIONS: The patients in our study underwent surgical resection of rectovaginal endometriosis and interventions included shave, disc resection, and segmental resection of the bowel. All patients underwent a preoperative transvaginal ultrasound to assess the extent of endometriosis. MEASUREMENTS AND MAIN RESULTS: There were 206 rectal shaves (90.4%), 2 disc resections (0.9%), and 20 segmental bowel resections (8.8%). A multivariable analysis demonstrated an association between bowel resection and ≥2 nodules located in the rectovaginal space (odds ratio [OR] 6.85; 95% confidence interval [CI], 1.37-34.2), nodules in the vesicouterine pouch (OR 5.87; 95% CI, 1.03-33.3), and increasing nodule size (OR 2.39 per 1 cm increase per 1 cm diameter increase; 95% CI, 1.56-3.64). CONCLUSION: Ultrasound findings of endometriotic nodule location, number of nodules, and increasing size are independent predictors of segmental bowel resection at the time of surgery for rectovaginal endometriosis. This highlights the importance of accurate diagnostic evaluation to aid counseling and surgical planning in the preoperative setting for women with rectovaginal endometriosis.

Cognitive and behavioral effects of cannabidiol in patients with treatment-resistant epilepsy.

PURPOSE: Therapeutic use of cannabidiol (CBD) in intractable epilepsies has increased considerably over the last ten years. As more evidence for the potentially beneficial effects of CBD on different epilepsy types is emerging, it is important to monitor potential cognitive and behavioral side effects. So far, studies including standardized neuropsychological data in the context of treatment with CBD in epilepsy patients are sparse. The present open-label study examines cognitive and behavioral effects of CBD in children and adults with treatment resistant epilepsy. METHOD: Thirty-nine patients with treatment-resistant epilepsy completed the study protocol, i.e. they were tested at baseline (T0) and after three months of CBD treatment (T1). Patients completed standardized neuropsychological tests on memory, executive functions and attention if they were capable. For cognitively impaired patients who could not complete cognitive tests, caregiver interviews were conducted and caregiver questionnaires completed. RESULTS: Significant cognitive decline from T0 to T1 was observed on none of the included measures. There was a significant improvement on a measure of selective attention and on a caregiver-rated behavioral measure. More than 89% of all individual test results remained stable or showed reliable improvement from T0 to T1. Cognitive and behavioral changes from T0 to T1 were not significantly correlated with CBD dose. Improvements in short-term/working memory were significantly related to better therapy response. CONCLUSION: No adverse group-level effects of CBD treatment were detected. On an individual level, most test results remained stable or were improved. Cognitive change was not related to CBD dose. The present results show that, from a cognitive and behavioral point of view, CBD seems to have an encouraging side-effect profile. The results need to be replicated with larger samples.

Effect of Local Anesthetics on Postoperative Pain in Patients Undergoing Gynecologic Laparoscopy: A Systematic Review and Meta-analysis of Randomized Trials.

OBJECTIVE: Pain remains a common complication after gynecologic laparoscopy. Use of local anesthesia may be beneficial in reducing postoperative pain. We performed a systematic review and meta-analysis to assess whether local anesthetic decreases postoperative pain after laparoscopic gynecologic procedures. DATA SOURCES: We searched Cumulative Index to Nursing and Allied Health Literature, Embase, and Medline from inception to November 2020 using Medical Subject Headings and free text combinations. METHODS OF TRIAL SELECTION: We included randomized controlled trials of patients undergoing gynecologic laparoscopy receiving port site subcutaneous, subfascial, or intraperitoneal local anesthetic compared with placebo or no intervention. We included 20 trials (1861 participants) with size varying between 28 and 164 participants. TABULATIONS, INTEGRATION, AND RESULTS: Meta-analysis was performed with RevMan 5.3 (Cochrane Collaboration, London, United Kingdom), with standard mean differences (SMDs) and random-effects model. Port site infiltration reduces postoperative pain at 4 hours (SMD -0.25; 95% confidence interval [CI], -0.44 to -0.06; 4 trials; 545 participants) and 6 hours (SMD -0.44; 95% CI, -0.82 to -0.06; 4 trials; 455 participants) after surgery. The administration of intraperitoneal local anesthetics reduces pain at 6 hours (-1.42; 95% CI, -3.22 to -0.30; 4 trials; 277 participants) after surgery. CONCLUSIONS: The use of port site and intraperitoneal local anesthetic decreases immediate postoperative pain in patients undergoing gynecologic laparoscopy, although its impact on analgesia requirements is unclear. Routine usage of local anesthetics should be considered for people undergoing gynecologic laparoscopy.

Health economic benefits through the use of diagnostic support systems and expert knowledge.

BACKGROUND: Rare diseases are difficult to diagnose. Due to their rarity, heterogeneity, and variability, rare diseases often result not only in extensive diagnostic tests and imaging studies, but also in unnecessary repetitions of examinations, which places a greater overall burden on the healthcare system. Diagnostic decision support systems (DDSS) optimized by rare disease experts and used early by primary care physicians and specialists are able to significantly shorten diagnostic processes. The objective of this study was to evaluate reductions in diagnostic costs incurred in rare disease cases brought about by rapid referral to an expert and diagnostic decision support systems. METHODS: Retrospectively, diagnostic costs from disease onset to diagnosis were analyzed in 78 patient cases from the outpatient clinic for rare inflammatory systemic diseases at Hannover Medical School. From the onset of the first symptoms, all diagnostic measures related to the disease were taken from the patient files and documented for each day. The basis for the health economic calculations was the Einheitlicher Bewertungsmaßstab (EBM) used in Germany for statutory health insurance, which assigns a fixed flat rate to the various medical services. For 76 cases we also calculated the cost savings that would have been achieved by the diagnosis support system Ada DX applied by an expert. RESULTS: The expert was able to achieve significant savings for patients with long courses of disease. On average, the expert needed only 27 % of the total costs incurred in the individual treatment odysseys to make the correct diagnosis. The expert also needed significantly less time and avoided unnecessary examination repetitions. If a DDSS had been applied early in the 76 cases studied, only 51-68 % of the total costs would have incurred and the diagnosis would have been made earlier. Earlier diagnosis would have significantly reduced costs. CONCLUSION: The study showed that significant savings in the diagnostic process of rare diseases can be achieved through rapid referral to an expert and the use of DDSS. Faster diagnosis not only achieves savings, but also enables the right therapy and thus an increase in the quality of life for patients.

Algorithm Change Protocols in the Regulation of Adaptive Machine Learning-Based Medical Devices.

One of the greatest strengths of artificial intelligence (AI) and machine learning (ML) approaches in health care is that their performance can be continually improved based on updates from automated learning from data. However, health care ML models are currently essentially regulated under provisions that were developed for an earlier age of slowly updated medical devices-requiring major documentation reshape and revalidation with every major update of the model generated by the ML algorithm. This creates minor problems for models that will be retrained and updated only occasionally, but major problems for models that will learn from data in real time or near real time. Regulators have announced action plans for fundamental changes in regulatory approaches. In this Viewpoint, we examine the current regulatory frameworks and developments in this domain. The status quo and recent developments are reviewed, and we argue that these innovative approaches to health care need matching innovative approaches to regulation and that these approaches will bring benefits for patients. International perspectives from the World Health Organization, and the Food and Drug Administration's proposed approach, based around oversight of tool developers' quality management systems and defined algorithm change protocols, offer a much-needed paradigm shift, and strive for a balanced approach to enabling rapid improvements in health care through AI innovation while simultaneously ensuring patient safety. The draft European Union (EU) regulatory framework indicates similar approaches, but no detail has yet been provided on how algorithm change protocols will be implemented in the EU. We argue that detail must be provided, and we describe how this could be done in a manner that would allow the full benefits of AI/ML-based innovation for EU patients and health care systems to be realized.

Long-lived particles at the energy frontier: the MATHUSLA physics case.

We examine the theoretical motivations for long-lived particle (LLP) signals at the LHC in a comprehensive survey of standard model (SM) extensions. LLPs are a common prediction of a wide range of theories that address unsolved fundamental mysteries such as naturalness, dark matter, baryogenesis and neutrino masses, and represent a natural and generic possibility for physics beyond the SM (BSM). In most cases the LLP lifetime can be treated as a free parameter from the [Formula: see text]m scale up to the Big Bang Nucleosynthesis limit of [Formula: see text] m. Neutral LLPs with lifetimes above [Formula: see text]100 m are particularly difficult to probe, as the sensitivity of the LHC main detectors is limited by challenging backgrounds, triggers, and small acceptances. MATHUSLA is a proposal for a minimally instrumented, large-volume surface detector near ATLAS or CMS. It would search for neutral LLPs produced in HL-LHC collisions by reconstructing displaced vertices (DVs) in a low-background environment, extending the sensitivity of the main detectors by orders of magnitude in the long-lifetime regime. We study the LLP physics opportunities afforded by a MATHUSLA-like detector at the HL-LHC, assuming backgrounds can be rejected as expected. We develop a model-independent approach to describe the sensitivity of MATHUSLA to BSM LLP signals, and compare it to DV and missing energy searches at ATLAS or CMS. We then explore the BSM motivations for LLPs in considerable detail, presenting a large number of new sensitivity studies. While our discussion is especially oriented towards the long-lifetime regime at MATHUSLA, this survey underlines the importance of a varied LLP search program at the LHC in general. By synthesizing these results into a general discussion of the top-down and bottom-up motivations for LLP searches, it is our aim to demonstrate the exceptional strength and breadth of the physics case for the construction of the MATHUSLA detector.

Neutrinoless Double-ß Decay with Nonstandard Majoron Emission.

We present a novel mode of neutrinoless double-ß decay with emission of a light Majoron-like scalar particle ϕ. We assume it couples via an effective seven-dimensional operator with a (V+A) lepton current and (V±A) quark currents leading to a long-range contribution that is unsuppressed by the light neutrino mass. We calculate the total double-ß decay rate and determine the fully differential shape for this mode. We find that future double-ß decay searches are sensitive to scales of the order Λ_{NP}≈1 TeV for the effective operator and a light scalar m_{ϕ}<0.2 MeV, based on ordinary double-ß decay Majoron searches. The angular and energy distributions can deviate considerably from that of two-neutrino double-ß decay, which is the main background. We point out possible ultraviolet completions where such an effective operator can emerge.

Effects of cannabidiol on brivaracetam plasma levels.

The use of cannabidiol (CBD) for treatment of pharmacoresistant epilepsies is increasing. CBD is metabolized via UDP-glucuronosyltransferase (UGT) and cytochrome 450 (CYP) enzymes, but information on interactions with common anticonvulsive drugs is incomplete. We report a case series of five patients receiving adjunctive treatment with CBD who showed increases in brivaracetam (BRV) levels by 95% to 280%. Only two patients reported mild adverse events, leading to a reduction of BRV in one patient. One possible mechanism contributing at least partially to increasing BRV level is the inhibition of CYP2C19 by cannabidiol. Further pharmacokinetic studies are required to understand other possible mechanisms of brivaracetam-cannabidiol interaction.