Epilepsy management during difficult times

Major disruption in the delivery of healthcare services can occur in exceptional situations such as natural disasters, conflicts, periods of severe economic hardship, and epidemics. These disruptions typically affect to the greatest extent the most vulnerable segments of the population, including people with epilepsy. Inability to access healthcare services can lead to failure to undergo necessary diagnostic investigations, or to receive needed therapeutic interventions, including epilepsy surgery. Stress and other factors associated with the nature or the cause of the disruption can adversely affect seizure control status, or precipitate the occurrence of psychiatric disorders and other comorbid conditions. Failure to access antiseizure medications is a common occurrence in these situations and can result in loss of seizure control, withdrawal seizures, and status epilepticus. In this article, we provide examples of recent disruptions in healthcare and their implications for people with epilepsy. We discuss the consequences of natural disasters, conflicts, economic sanctions, and focus in greater detail on lessons learnt during the COVID-19 pandemic. We also discuss possible mitigation procedures, focusing in particular on the application of telemedicine to epilepsy care. Finally, we underline the need for governments, healthcare authorities, and international organizations to improve their preparedness to deal with exceptional situations that may arise in the future

THE ROLE OF HYDROLOGIC DISTURBANCES ON BIOMASS EROSION DYNAMICS: FIRST RESULTS FROM RIVERINE EXPERIMENTS

This paper presents an overview of RIVERINE project (RIver-VEgetation interactions and Reproduction of Island Nuclei formation and Evolution) preliminary results. We show some exemplary statistics of the both eroded and non-eroded material as resulting from a competitive dynamics between vegetation growth time scale and interarrival time of disturbances with constant magnitude. Two experiments, that is within channels with either regular geometry (parallel walls) or converging walls are discussed. Results show coherency of the results between the two geometries as far as the selective erosion mechanism of riparian vegetation is concerned. The experiment with convergent walls also conjectures that island formation is limited by the stream power associated to the local specific discharge

Epilepsy priorities in Europe: A report of the ILAE-IBE Epilepsy Advocacy Europe Task Force.

The European Forum on Epilepsy Research (ERF2013), which took place in Dublin, Ireland, on May 26-29, 2013, was designed to appraise epilepsy research priorities in Europe through consultation with clinical and basic scientists as well as representatives of lay organizations and health care providers. The ultimate goal was to provide a platform to improve the lives of persons with epilepsy by influencing the political agenda of the EU. The Forum highlighted the epidemiologic, medical, and social importance of epilepsy in Europe, and addressed three separate but closely related concepts. First, possibilities were explored as to how the stigma and social burden associated with epilepsy could be reduced through targeted initiatives at EU national and regional levels. Second, ways to ensure optimal standards of care throughout Europe were specifically discussed. Finally, a need for further funding in epilepsy research within the European Horizon 2020 funding programme was communicated to politicians and policymakers participating to the forum. Research topics discussed specifically included (1) epilepsy in the developing brain; (2) novel targets for innovative diagnostics and treatment of epilepsy; (3) what is required for prevention and cure of epilepsy; and (4) epilepsy and comorbidities, with a special focus on aging and mental health. This report provides a summary of recommendations that emerged at ERF2013 about how to (1) strengthen epilepsy research, (2) reduce the treatment gap, and (3) reduce the burden and stigma associated with epilepsy. Half of the 6 million European citizens with epilepsy feel stigmatized and experience social exclusion, stressing the need for funding trans-European awareness campaigns and monitoring their impact on stigma, in line with the global commitment of the European Commission and with the recommendations made in the 2011 Written Declaration on Epilepsy. Epilepsy care has high rates of misdiagnosis and considerable variability in organization and quality across European countries, translating into huge societal cost (0.2% GDP) and stressing the need for cost-effective programs of harmonization and optimization of epilepsy care throughout Europe. There is currently no cure or prevention for epilepsy, and 30% of affected persons are not controlled by current treatments, stressing the need for pursuing research efforts in the field within Horizon 2020. Priorities should include (1) development of innovative biomarkers and therapeutic targets and strategies, from gene and cell-based therapies to technologically advanced surgical treatment; (2) addressing issues raised by pediatric and aging populations, as well as by specific etiologies and comorbidities such as traumatic brain injury (TBI) and cognitive dysfunction, toward more personalized medicine and prevention; and (3) translational studies and clinical trials built upon well-established European consortia

final safety tolerability and seizure outcomes in patients with focal epilepsy treated with adjunctive perampanel for up to 4 years in an open label extension of phase iii randomized trials study 307

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Reduction of Steady-State Valproate Levels by Other Antiepileptic Drugs

Steady-state plasma valproate (VPA) levels were analyzed in 37 children after 6 weeks of VPA therapy. Twenty-six patients were receiving other antiepileptic drugs in addition to VPA (experimental group). Eleven patients who received VPA alone served as controls. The mean VPA dose was not statistically different for the two groups (experimental group, 35.4 mg/kg/ day, 11.6 SD; control group, 31.1 mg/kg/day, SD 6.6) The mean plasma VPA level was significantly lower for the experimental group (63.0 Μg/m1, SD 21.8) than for the control (99.3 Μg/m1), SD 23.3) ( p < 0.01). VPA levelrdose ratio (LDR) was also reduced in the experimental group (1.92, SD 0.75) as compared to controls (3.26, SD 0.65) ( p < 0.01). Within the experimental group the VPA levels and VPA LDR were significantly reduced in patients receiving either phenytoin or phenobarbital. The data suggest that other antiepileptic drugs significantly alter the steady-state level to dose relationship for VPA. RÉSUMÉ Le taux plasmatique À l'Équilibre du valproate de sodium (VPA) a ÉtÉÉtudiÉ chez 37 enfants aprÈs 6 semaines de thÉrapeutique. Vingt six patients reÇoivent d'autres mÉdicaments antiÉpileptiques associÉs au VPA (groupe expÉrimental) alors que 11 sujets tÉmoins ne reÇoivent que le VPA seul. La posologie moyenne du VPA n'est pas significativement diffÉrente entre les deux groupes (35,4 mg/kg/jour ± 11,6 centre 31,1 mg/kg/jour ± 6,6). Le taux plasmatique de VPA est significativement plus bas dans le groupe experimental (63,0 Μg/ml ± 21,8) contre 99,3 Μg/ml ± 23,3 dans le groupe tÉmoin ( p < 0,01). Le rapport taux plasmatique/posologie (LDR) a ÉtÉ diminuÉ dans le groupe expÉrimental (1,92 ± 0,75) par rapport au groupe tÉmoin (3,26 ± 0,65), p < 0,01 en particulier chez les malades recevant de la phÉnytoÏne ou du phÉnobarbital. La posologie moyenne du VPA n'Étant pas significativement diffÉrente dans les deux groupes, les faits observÉs suggÈrent que l'addition d'autres antiÉpileptiques est capable de modifier le taux À l'Équilibre du VPA plasmatique en fonction de la dose administrÉe. RESUMEN Se analizaron los niveles estables de valproato en plasma (VPA) en 37 niÑos despuÉs de 6 semanas de terapia con VPA. Ventiseis pacientes recibÍan otros fÁrmacos ademÁs de VPA (grupo experimental) y once sÓlo tomaban VPA y sirvieron como controles. La dosis media de VPA no fue significativamente distinta en los dos grupos (grupo experimental: 35,4 mg/kg/dÍa, DS 11,6; grupo control: 31.1 mg/kg/dÍa, DS 6,6). El nivel plasmÁtico medio de VPA fue significativamente inferior en el grupo experimental (63,0 Μg/ml, DS 21,8) que en el control (99,3 Μg/ml, DS 23,3), p < 0,01. La relaciÓn nivel de VPA: dosis (LDR) estaba tambiÉn reducida en el grupo experimental (1,92, DS 0,75) al compararla con los controles (3,26, DS 0,65), p < 0,01. Dentro del grupo experimental los niveles de VPA y la LDR estaban significativamente reducidos en pacientes que tomaban fenitoÍna o fenobarbital. La dosis media no fue diferente entre los grupos experimental y control. Estos datos sugieren que la ingestiÓn de otros fÁrmacos alteran de modo significativo los niveles estables de VPA en relaciÓn con la dosis. ZUSAMMENFASSUNG In steady-state befindliche Plasma Valproatspiegel (VPA) wurden bei 37 Kindern nach 6 wÖchiger VPA-Therapie analysiert. 26 Patienten erhielten zusÄtzlich zum VPA andere Antiepileptika (experimentelle Gruppe). 11 Patienten, die VPA alleine bekamen, dienten als Kontrollen. Die mittlere VPA-Dosis war in beiden Gruppen nicht signifikant Vunterschiedlich (experimentelle Gruppe 35,4 mg/kg pro Tag, 11,6 SD; Kontrollgruppe 31,1 mg/kg pro Tag, SD 6,6). Der mittlere Plasma VPA-Spiegel war signifikant niedriger in der experimentellen Gruppe (63,0 Μg/ml, SD 21,8) als in der Kontrollgruppe (99,3 Μg/m1, SD 23,3), p < 0.01. Das VerhÄltnis VPA-Spiegel: Dosis (LDR) war in der experimentellen Gruppe ebenfalls reduziert (1,92, SD 0,75) gegenuber der Kontrollgruppe (3,26, SD 0,65), p < 0.01. Innerhalb der experimentellen Gruppe waren die VPA-Spiegel und die VPA/LDR bei Patienten, die entweder Phenytoin oder Phenobarbital bekamen, signifikant erniedrigt. Die mittlere VPA-Dosis war nicht signifikant unterschiedlich in der experimentellen und in der Kontrollgruppe. Diese Daten lassen vermuten, daß andere Antiepileptika signifikanterweise den Steady-state-Spiegel im Hinblick auf die verabfolgte Dosis VPA Ändern.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66058/1/j.1528-1157.1981.tb06154.x.pd

Toward responsible clinical n-of-1 strategies for rare diseases

N-of-1 strategies can provide high-quality evidence of treatment efficacy at the individual level and optimize evidence-based selection of off-label treatments for patients with rare diseases. Given their design characteristics, n-of-1 strategies are considered to lay at the intersection between medical research and clinical care. Therefore, whether n-of-1 strategies should be governed by research or care regulations remains a debated issue. Here, we delineate differences between medical research and optimized clinical care, and distinguish the regulations which apply to either. We also set standards for responsible optimized clinical n-of-1 strategies with (off-label) treatments for rare diseases. Implementing clinical n-of-1 strategies as defined here could aid in optimized treatment selection for such diseases

Validated outcome of treatment changes according to International League Against Epilepsy criteria in adults with drug-resistant focal epilepsy.

OBJECTIVE: Although many studies have attempted to describe treatment outcomes in patients with drug-resistant epilepsy, results are often limited by the adoption of nonhomogeneous criteria and different definitions of seizure freedom. We sought to evaluate treatment outcomes with a newly administered antiepileptic drug (AED) in a large population of adults with drug-resistant focal epilepsy according to the International League Against Epilepsy (ILAE) outcome criteria. METHODS: This is a multicenter, observational, prospective study of 1053 patients with focal epilepsy diagnosed as drug-resistant by the investigators. Patients were assessed at baseline and 6, 12, and 18 months, for up to a maximum of 34 months after introducing another AED into their treatment regimen. Drug resistance status and treatment outcomes were rated according to ILAE criteria by the investigators and by at least two independent members of an external expert panel (EP). RESULTS: A seizure-free outcome after a newly administered AED according to ILAE criteria ranged from 11.8% after two failed drugs to 2.6% for more than six failures. Significantly fewer patients were rated by the EP as having a "treatment failure" as compared to the judgment of the investigator (46.7% vs 62.9%, P < 0.001), because many more patients were rated as "undetermined outcome" (45.6% vs 27.7%, P < 0.001); 19.3% of the recruited patients were not considered drug-resistant by the EP. SIGNIFICANCE: This study validates the use of ILAE treatment outcome criteria in a real-life setting, providing validated estimates of seizure freedom in patients with drug-resistant focal epilepsy in relation to the number of previously failed AEDs. Fewer than one in 10 patients achieved seizure freedom on a newly introduced AED over the study period. Pseudo drug resistance could be identified in one of five cases

New trajectories of the Hungarian regional development: balanced and rush growth of territorial capital

The basic assumption of the paper is that numerous similarities exist between the patterns of economic growth and territorial capital growth. The rush economic growth and rush growth of territorial capital are compared empirically at Hungarian micro-regional level from 2004 until 2010. After normalizing the dataset, a very novel spatial econometric method is applied, called a penalty for bottleneck. The results show that the constant rush growth of territorial capital is as harmful as economic recession. On the other hand, the decrease of infrastructural and social capital caused the rush growth of territorial capital in this period. Moreover, the key findings of two case studies suggest that the balanced growth of territorial capital will be created by the falling social inequalities and increasing infrastructural capita

The serine protease hepsin mediates urinary secretion and polymerisation of Zona Pellucida domain protein uromodulin.

Uromodulin is the most abundant protein in the urine. It is exclusively produced by renal epithelial cells and it plays key roles in kidney function and disease. Uromodulin mainly exerts its function as an extracellular matrix whose assembly depends on a conserved, specific proteolytic cleavage leading to conformational activation of a Zona Pellucida (ZP) polymerisation domain. Through a comprehensive approach, including extensive characterisation of uromodulin processing in cellular models and in specific knock-out mice, we demonstrate that the membrane-bound serine protease hepsin is the enzyme responsible for the physiological cleavage of uromodulin. Our findings define a key aspect of uromodulin biology and identify the first in vivo substrate of hepsin. The identification of hepsin as the first protease involved in the release of a ZP domain protein is likely relevant for other members of this protein family, including several extracellular proteins, as egg coat proteins and inner ear tectorins