Effectiveness and tolerability of adjunctive brivaracetam in patients with focal seizures: second interim analysis of 6-month data from a prospective observational study in Europe

Brivaracetam (BRV) is indicated for adjunctive treatment of focal (partial-onset) seizures with or without secondary generalisation in patients 4 years of age and older in the European Union (EU). An ongoing 12-month, prospective, non-interventional post-marketing study (EP0077; NCT02687711) is collecting real-world information on patients receiving treatment with adjunctive BRV in Europe. In this study, BRV is prescribed according to routine clinical practice and the EU Summary of Product Characteristics. This second interim analysis assessed effectiveness, tolerability and health-related quality of life outcomes for up to 6 months of treatment. At the cut-off date (13 April 2018), 266 patients from five countries had attended Visit 1, 24.1% (64/266) had completed the study, 37.6% (100/266) were ongoing, and 38.3% (102/266) had discontinued. In total, 261 patients had at least one dose of BRV and were included in the analyses. Patients had a mean time since epilepsy diagnosis of 23.2 years, a mean of eight lifetime AEDs (sum of AEDs discontinued prior to study entry and concomitant at study entry), and a median of five focal seizures per 28 days during the 3-month retrospective Baseline. 66.3% of patients initiated BRV at a dose within the recommended starting range (50–100 mg/day) and 87.1% of patients received BRV modal doses within the recommended dose range (50–200 mg/day) during the study. Retention rates were 79.1% (N = 239) at 3 months and 62.1% (N = 211) at 6 months. The 50% responder rates for focal seizures were 46.8% (N = 139) at 3 months and 53.6% (N = 97) at 6 months. The proportions of patients who were seizure-free were 10.7% (21/196) and 7.5% (15/199) at 3 and 6 months of treatment, respectively. Median percent reductions in focal seizure frequency per 28 days from Baseline to 3 and 6 months were 34.6% (N = 139) and 53.3% (N = 97), respectively. Overall, 44.2% of patients had an improvement and 15.4% had a worsening in Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 total score from Baseline to 6 months (N = 52). At least one treatment-emergent adverse event (TEAE) was reported in 51.0% (133/261) of patients, and 34.5% (90/261) of patients had drug-related TEAEs. The most common drug-related TEAEs (≥5% of patients) were drug ineffective (7.7%), seizure (6.5%), and fatigue (6.1%). In this 6-month interim analysis, BRV showed effectiveness when used in clinical practice in five European countries. BRV was well tolerated, and no new safety signals were observed

Intra-articular Injection Administration in UK Ex-professional Footballers During Their Playing Careers and the Association with Post-career Knee Osteoarthritis

© 2020, The Author(s). Background: The long-term risk from knee intra-articular (KIA) injections in professional athletes such as ex-footballers remains unknown. The use of KIA injections is controversial and remains anecdotally prolific as it is perceived as being safe/beneficial. The aim of this study was to determine the number, type and frequency KIA injections administered to retired professional footballers during their playing careers and the associations with post-career knee osteoarthritis (KOA). Methods: This is a cross-sectional study involving a postal questionnaire (n = 1207) and subsequent knee radiographs in a random sample of questionnaire responders (n = 470). Footballers self-reported in the questionnaire whether they had received KIA injections and the estimated total number over the course of their playing career. Participant characteristics and football career-related details were also recorded. KOA was measured as self-reported knee pain (KP), total knee replacement (TKR) and radiographic KOA (RKOA). Results: 44.5% of footballers had received at least one KIA injection (mean: 7.5; SD ± 11.2) during their professional career. 71% of knee injections were cortisone/corticosteroid based. Multivariate logistic regression, adjusting for age, body mass index (BMI) and significant knee injury identified that footballers with injections weretwo times more likely to have KP (OR 1.81, 95% CI 1.40–2.34) and TKR (OR 2.21, 95% CI 1.43–3.42) than those without injections. However, there was no association with RKOA (OR 1.30, 95% CI 0.85–2.01). Given, the association with KP and TKR, we found a significant dose–response relationship as the more injections a player received (by dose–response groups), the greater the risk of KP and TKR outcomes after adjustment for knee injury and other confounders (p for trend < 0.01). Conclusion: On average, 8 KIA injections were given to the ex-footballers during their professional career. The most commonly administered injections were cortisone based. These injections associated with KP and TKR after they retired. The associations are independent of knee injuries and are dose dependent. The study suggests that there may have been excessive use of KIA injections to expedite return to play and this contributed to detrimental long-term outcomes such as KP and TKR post-retirement from professional football

Attenuated CSF-1R signalling drives cerebrovascular pathology

Cerebrovascular pathologies occur in up to 80% of cases of Alzheimer's disease; however, the underlying mechanisms that lead to perivascular pathology and accompanying blood-brain barrier (BBB) disruption are still not fully understood. We have identified previously unreported mutations in colony stimulating factor-1 receptor (CSF-1R) in an ultra-rare autosomal dominant condition termed adult-onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP). Cerebrovascular pathologies such as cerebral amyloid angiopathy (CAA) and perivascular p-Tau were some of the primary neuropathological features of this condition. We have identified two families with different dominant acting alleles with variants located in the kinase region of the CSF-1R gene, which confer a lack of kinase activity and signalling. The protein product of this gene acts as the receptor for 2 cognate ligands, namely colony stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). Here, we show that depletion in CSF-1R signalling induces BBB disruption and decreases the phagocytic capacity of peripheral macrophages but not microglia. CSF-1R signalling appears to be critical for macrophage and microglial activation, and macrophage localisation to amyloid appears reduced following the induction of Csf-1r heterozygosity in macrophages. Finally, we show that endothelial/microglial crosstalk and concomitant attenuation of CSF-1R signalling causes re-modelling of BBB-associated tight junctions and suggest that regulating BBB integrity and systemic macrophage recruitment to the brain may be therapeutically relevant in ALSP and other Alzheimer's-like dementias

The rhetoric and reality of integrated patient-centered care for healthcare providers: An ethnographic exploration of epilepsy care in Ireland

In line with healthcare reform across the world, the National Clinical Programme for Epilepsy (NCPE) in Ireland describes a model that aims to achieve holistic integrated person (patient)-centered care (PCC). While generally welcomed by stakeholders, the steps required to realize the NCPE ambition and the preparedness of those involved to make the journey are not clear. This study explored the perceptions of healthcare providers in the Irish epilepsy care ecosystem to understand their level of readiness to realize the benefits of an integrated PCC model. Ethnographic fieldwork including observations of different clinical settings across three regions in Ireland and one-to-one interviews with consultant epileptologists (n = 3), epilepsy specialist nurses (n = 5), general practitioners (n = 4), and senior healthcare managers (n = 3) were conducted. While there is a person-centered ambiance and a disposition toward advancing integrated PCC, there are limits to the readiness of the epilepsy care environment to fully meet the aspirations of healthcare reform. These are the following: underdeveloped healthcare partnerships;, poor care coordination;, unintended consequences of innovation;, and tension between pace and productivity. In the journey from policy to practice, the following multiple tensions collide: policy aims to improve services for all patients while simultaneously individualizing care; demands for productivity limit the time and space required to engage in incremental and iterative improvement initiatives. Understanding these tensions is an essential first step on the pathway to integrated PCC implementation

Heritability of subcortical volumetric traits in mesial temporal lobe epilepsy.

OBJECTIVES: We aimed to 1) determine if subcortical volume deficits are common to mesial temporal lobe epilepsy (MTLE) patients and their unaffected siblings 2) assess the suitability of subcortical volumetric traits as endophenotypes for MTLE. METHODS: MRI-based volume measurements of the hippocampus, amygdala, thalamus, caudate, putamen and pallidium were generated using an automated brain reconstruction method (FreeSurfer) for 101 unrelated 'sporadic' MTLE patients [70 with hippocampal sclerosis (MTLE+HS), 31 with MRI-negative TLE], 83 unaffected full siblings of patients and 86 healthy control subjects. Changes in the volume of subcortical structures in patients and their unaffected siblings were determined by comparison with healthy controls. Narrow sense heritability was estimated ipsilateral and contralateral to the side of seizure activity. RESULTS: MTLE+HS patients displayed significant volume deficits across the hippocampus, amygdala and thalamus ipsilaterally. In addition, volume loss was detected in the putamen bilaterally. These volume deficits were not present in the unaffected siblings of MTLE+HS patients. Ipsilaterally, the heritability estimates were dramatically reduced for the volume of the hippocampus, thalamus and putamen but remained in the expected range for the amygdala. MRI-negative TLE patients and their unaffected siblings showed no significant volume changes across the same structures and heritability estimates were comparable with calculations from a healthy population. CONCLUSIONS: The findings indicate that volume deficits for many subcortical structures in 'sporadic' MTLE+HS are not heritable and likely related to acquired factors. Therefore, they do not represent suitable endophenotypes for MTLE+HS. The findings also support the view that, at a neuroanatomical level, MTLE+HS and MRI-negative TLE represent two distinct forms of MTLE

Are patients ready for integrated person-centered care? A qualitative study of people with epilepsy in Ireland

The National Clinical Programme for Epilepsy (NCPE) in Ireland aims to deliver a holistic model of integrated person-centered care (PCC) that addresses the full spectrum of biomedical and psychosocial needs of people with epilepsy (PwE). However, like all strategic plans, the model encompasses an inherent set of assumptions about the readiness of the environment to implement and sustain the actions required to realize its goals. In this study, through the lens of PwE, the Irish epilepsy care setting was explored to understand its capacity to adopt a new paradigm of integrated PCC. Focus groups and semi-structured one-to-one interviews were employed to capture the qualitative experiences of a sample of Irish PwE (n = 27) in the context of the care that they receive. Participants were from different regions of the country and were aged between 18 and 55 years with 1 to 42 years since diagnosis (YSD). Highlighting a gap between policy intent and action on the ground, findings suggest that patient readiness to adopt a new model of care cannot be assumed. Expectations, preferences, behaviors, and values of PwE may sustain the more traditional constructions of healthcare delivery rather than the integrated PCC goals of reform. These culturally constituted perceptions illustrate that PwE do not instinctively appreciate the goals of healthcare reform nor the different behavior expected from them within a reformed healthcare system. Recalibrating deep-rooted patient views is necessary to accomplish the aspirations of integrated PCC. Patient engagement emphasizing the meaningful role that they can play in shaping their healthcare services is vital

Risk Factors for Knee Osteoarthritis in Retired Professional Footballers: A Cross-Sectional Study

Objective: To determine risk factors for three knee osteoarthritis (KOA) outcomes, knee pain (KP), radiographic KOA (RKOA) and total knee replacement (TKR), in professional footballers.Design: This was a cross-sectional study involving a postal questionnaire, followed by radiographic assessment in a sub-cohort of responders. Settings and Participants: 4775 questionnaires were sent to retired professional footballers, who had played in the English football league, and 1207 responded. Of these, 470 underwent knee radiographs. Assessment of Risk Factors: Potential factors include age, BMI, knee alignment, a history of football-related knee injury, and training hours (during career) were collected via the questionnaire.Main Outcome Measures: KOA outcomes were current KP (pain for most days of the previous month), TKR (self-reported) and RKOA (observed via radiographs). Results: Football-related injury was the strongest risk factor for KP [aOR 4.22, 95%CI 3.26-5.48], RKOA [aOR 2.88, 95%CI 1.81-4.59] and TKR [aOR 4.83, 95%CI 2.87-8.13]. Footballers had a 7% increased risk of RKOA for every 1000 hours trained. While age and gout were associated with all three KOA outcomes, BMI, nodal OA, a family history of OA, knee malalignment and 2D:4D ratio were associated with one or another of these three KOA outcomes.Conclusion: This study is the first to examine KOA risk factors in retired professional footballers. The study has identified several risk factors, both specific (for example, knee injury and training dose), and non-specific (for example, age and gout) to footballers. This may be used to develop prevention strategies to reduce the risk of KOA in professional footballers following retirement

Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kB-dependent manner

Hepatocyte death is an important contributing factor in a number of diseases of the liver. PHD1 confers hypoxic sensitivity upon transcription factors including the hypoxia inducible factor (HIF) and nuclear factor-kappaB (NF-κB). Reduced PHD1 activity is linked to decreased apoptosis. Here, we investigated the underlying mechanism(s) in hepatocytes. Basal NF-κB activity was elevated in PHD1(-/-) hepatocytes compared to wild type controls. ChIP-seq analysis confirmed enhanced binding of NF-κB to chromatin in regions proximal to the promoters of genes involved in the regulation of apoptosis. Inhibition of NF-κB (but not knock-out of HIF-1 or HIF-2) reversed the anti-apoptotic effects of pharmacologic hydroxylase inhibition. We hypothesize that PHD1 inhibition leads to altered expression of NF-κB-dependent genes resulting in reduced apoptosis. This study provides new information relating to the possible mechanism of therapeutic action of hydroxylase inhibitors that has been reported in pre-clinical models of intestinal and hepatic disease.status: publishe

Dynamic Blood-Brain Barrier Regulation in Mild Traumatic Brain Injury

Whereas the diagnosis of moderate and severe traumatic brain injury (TBI) is readily visible on current medical imaging paradigms (magnetic resonance imaging [MRI] and computed tomography [CT] scanning), a far greater challenge is associated with the diagnosis and subsequent management of mild TBI (mTBI), especially concussion which, by definition, is characterized by a normal CT. To investigate whether the integrity of the blood-brain barrier (BBB) is altered in a high-risk population for concussions, we studied professional mixed martial arts (MMA) fighters and adolescent rugby players. Additionally, we performed the linear regression between the BBB disruption defined by increased gadolinium contrast extravasation on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on MRI and multiple biomechanical parameters indicating the severity of impacts recorded using instrumented mouthguards in professional MMA fighters. MMA fighters were examined pre-fight for a baseline and again within 120 h post-competitive fight, whereas rugby players were examined pre-season and again post-season or post-match in a subset of cases. DCE-MRI, serological analysis of BBB biomarkers, and an analysis of instrumented mouthguard data, was performed. Here, we provide pilot data that demonstrate disruption of the BBB in both professional MMA fighters and rugby players, dependent on the level of exposure. Our data suggest that biomechanical forces in professional MMA and adolescent rugby can lead to BBB disruption. These changes on imaging may serve as a biomarker of exposure of the brain to repetitive subconcussive forces and mTBI

A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam

OBJECTIVE: Levetiracetam (LEV) is an effective anti-seizure medicine, but 10-20% of people treated with LEV report psychiatric side-effects and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioural ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioural disorder (n=149) or psychotic reaction (n=37) to LEV-exposed people with no history of psychiatric ADRs (n=920). All samples were of European ancestry. We performed GWAS analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n=18) and controls (n=122). RESULTS: Univariate GWAS found no significant associations with either LEV-ADR. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to controls (p = 0.0097, estimate = 0.4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. SIGNIFICANCE: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV-ADRs