Pregabalin for the management of partial epilepsy

Pregabalin is one of the latest antiepileptic drugs introduced for the treatment of partial epilepsy. Its efficacy and safety as adjunctive therapy in refractory partial epilepsy have been established in four double-blind placebo-controlled trials (n = 1396) and 4 long-term open-label studies (n = 1480). In 3 fixed-dose trials, the proportion of patients with a ≥50% reduction in seizure frequency across the effective dose-range (150–600 mg/day) ranged between 14% and 51%, with a clear dose-response relationship. Suppression of seizure activity could be demonstrated as early as day 2. The most frequently reported CNS-related adverse events included dizziness, somnolence, ataxia and fatigue, were usually mild or moderate, and tended to be dose related. In long-term studies, weight gain was reported as an adverse event by 24% of patients. When pregabalin dose was individualized to according to response within the 150 to 600 mg/day dose range, tolerability was considerably improved compared with use of a high-dose, fixed-dose regimen (600 mg/day) without titration. In long-term studies up to 4 years, no evidence of loss efficacy was identified. During the last year on pregabalin, 3.7% of patients were seizure-free. Pregabalin appears to be a useful addition to the therapeutic armamentariun for the management of refractory partial epilepsy

Refractory and super-refractory status epilepticus in adults: a 9-year cohort study.

While status epilepticus (SE) persisting after two antiseizure agents is called refractory (RSE), super-refractory status epilepticus (SRSE) defines SE continuing after general anaesthesia. Its prevalence and related clinical profiles have received limited attention, and most studies were restricted to intensive care facilities. We therefore aimed at describing RSE and SRSE frequencies and identifying associated clinical variables. Between 2006 and 2015, consecutive adult SE episodes were prospectively recorded in a registry. Occurrence of RSE and SRSE and their relationship to clinical variables of interest, including outcome, were analysed. Of 804 SE episodes, 268 (33.3%) were RSE and 33 (4%) SRSE. Coma induction for SE treatment occurred in 79 (9.8%) episodes. Severe consciousness impairment (OR 1.67; 95% CI 1.24-2.46; P = 0.001), increasing age (OR 1.01, 95% CI 1.01-1.02), and lack of remote symptomatic SE aetiology (OR 0.48; 95% CI 0.32-0.72) were independently associated with RSE, while severe consciousness impairment (OR 4.26; 95% CI 1.44-12.60) and younger age (OR 0.96; 95% CI 0.95-0.99) correlated with SRSE; however, most SRSE episodes were not predicted by these variables. Mortality was 15.5% overall, higher in RSE (24.5%) and SRSE (37.9%) than in non-refractory SE (9.8%) (P < 0.001). Super-refractory status epilepticus appears clearly less prevalent in this cohort than previously reported, probably as it is not restricted to intensive care unit. SRSE emerges in younger patients with marked consciousness impairment, pointing to the underlying severe clinical background, but these variables do not predict most SRSE developments. There is currently a knowledge gap for prediction of SRSE occurrence that needs to be filled

Synthese, Untersuchung und Anwendung supramolekularer Wirte in der chemischen Sensorik

Während dieser Arbeit wurden verschiedene Bereiche der molekularen Erkennung untersucht und deren Anwendung in supramolekularer Sensorik evaluiert. Im ersten Teil der Arbeit wurden Molekularstruktur-Affinitäts-Beziehungen untersucht, indem Substrat-Affinitätsprofile für eine Reihe von supramolekularen Wirten auf Basis von Tetraphenylmethan und 9,9‘-Spirobifluoren sowie für Wirte basierend auf Resorcin[4]aren mit einer Auswahl an niedermolekularen Analyten gemessen wurden. Hieraus konnten neue Erkenntnisse für das Design und die Synthesestrategie von Affinitätsmaterialien zur Anwendung auf Quarzmikrowaagen gewonnen werden. In der Rigiditätsstudie mit Tetraphenylmethan- und 9,9‘-Spirobifluoren-basierten supra-molekularen Materialien konnte die Überlegenheit des starren Spirobifluoren-Gerüsts gezeigt werden. Hierbei konnte der mit Isosteviol-Derivaten funktionalisierte Spirobifluoren-Grundkörper formstabilere Bindungsstellen ausbilden und so den Gastmolekülen einen prononcierteren Wechselwirkungsraum zur Verfügung stellen. Die systematische Untersuchung der Resorcin[4]aren-basierten supramolekularen Wirte auf ihre Affinität führte zum besseren Verständnis des Einflusses der Hohlraumstruktur, der Zugänglichkeit, der Größe sowie der Art der supramolekularen Wechselwirkungen der Wirtsmoleküle. Hierbei konnte gezeigt werden, dass Resorcin[4]aren-Kavitanden mit definierten, tiefen Kavitäten überlegene supramolekulare Eigenschaften gegenüber weit-offenen und sogar oben verbrückten Resorcin[4]aren-basierten Strukturen aufweisen. Im letzten Teil dieser Arbeit konnte ein neues System zur Detektion, Separation und Lagerung des umweltschädlichen FCKWs Trichlorfluormethan erarbeitet werden. In der Studie wurden planare Bragg-Gitter-Sensoren mit per-Methyl-, per-Ethyl- und per-Allyl-substituierten Cyclo¬dextrinen als Affinitätsmaterialien auf gasförmiges Trichlorfluormethan sensibilisiert. Diese Art der Funktionalisierung hat sich als hocheffizient in der Anwendung erwiesen, da im Vergleich zu einem identischen, aber unbeschichteten Sensor eine bis zu 400-fach höhere Signalantwort erzielt werden konnte. Die vorgestellte Sensorvorrichtung weist eine Nachweis¬¬grenze von bis zu 5 ppm auf. Es konnte ebenfalls eine Abhängigkeit der Adsorptions¬kinetik von der Substituentenlänge gezeigt werden. Auf der einen Seite nehmen die Reaktionszeiten des Sensors mit zunehmender Länge der Substituenten des Affinitäts-materials ab. Auf der anderen Seite konnte eine höhere Sensitivität bei per-Methylierten Cyclodextrinen beobachtet werden. Auf diese Weise konnte ein Sensorsystem zur Trichlor-fluormethan-Detektion realisiert und untersucht werden. Besonders interessante Ergebnisse konnten in Verbindung des Trichlorfluormethans mit per-Methyliertem -Cyclodextrin festgestellt werden. Es konnte die Fähigkeit von Hexakis(2,3,6-tri-O-methyl)-α-cyclodextrin nachgewiesen werden, selektiv einen sehr stabilen supra-molekularen Komplex mit Trichlorfluormethan auszubilden und so dauerhaft zu speichern. Die reversible Komplexierung führte zu einer hocheffizienten und stabilen Kristallisation im Verhältnis 4:1, welche sowohl kristallographisch, als auch thermogravimetrisch nachgewiesen wurde. Am Beispiel eines binären Gemisches aus Dichlormethan und Trichlorfluormethan konnte die außerordentliche Selektivität der Freon 11 Komplexierung innerhalb der Cyclodextrinkavität gezeigt werden. Darüber hinaus wurde die Anwendbarkeit von Hexakis(2,3,6-tri-O-methyl)-α-cyclodextrin als Packungsmaterial für eine Festbett-adsorption demonstriert und somit die Herstellung von wirtschaftlichen, wiederverwend-baren und hoch nachhaltigen Filterelementen für gasförmiges Trichlorfluormethan ermöglicht. Des Weiteren konnte gezeigt werden, dass bei Anwendung dieses Cyclodextrins als Affinitätsschicht auf planaren Bragg-Gitter-Sensoren eine CFC-11-Konzentrationen über 35 Vol% zu einer sichtbaren spontanen Kristallisation der per-Me -Cyclodextrin-Affinitäts-schicht auf der Sensoroberfläche führte, sodass dieses Verhalten effektiv als Einwegsensor adaptiert werden kann und so zum Beispiel zur Überwachung von industriellen Produktions-anlagen oder Anlagen zur Kühlgeräteentsorgung eingesetzt werden kann, um die Umwelt vor der Exposition mit dem schädlichen Trichlorfluormethan zu schützen.During this work, different areas of molecular recognition were investigated and their application in supramolecular sensor technology was evaluated. The results could be summarized in three publications and a manuscript in revision in internationally recognized (peer-reviewed) scientific journals as well as a patent application. In the first part of the study, molecular structure affinity relationships were investigated by measuring substrate affinity profiles for a number of supramolecular hosts based on tetraphenylmethane and 9,9'-spirobifluoren as well as for hosts based on resorcin[4]aren with a selection of low molecular weight analytes. From this, new insights for the design and synthesis strategy of affinity materials for application on quartz microbalances were obtained. In the rigidity study with tetraphenylmethane and 9,9'-spirobifluorene-based supra-molecular materials, the superiority of the rigid spirobifluorenic scaffold was demonstrated. Here, the spirobifluorene base functionalized with isosteviol derivatives could form more stable binding sites and thus provide the guest molecules with a more pronounced interaction space. This was demonstrated by significantly higher affinities using quartz microbalance analysis. The systematic investigation of the affinity of resorcinol[4]arene based supramolecular hosts led to a better understanding of the influence of cavity structure, accessibility, size and type of supramolecular interactions of the host molecules. These results inevitably led to the conclusion that the interaction of these factors is of extraordinary importance for gravimetric sensing. It could be shown that resorcinol[4]arene-cavitands with defined, deep cavities have superior supramolecular properties compared to widely open and even top-bridged resorcinol[4]arene-based structures. Furthermore, it was demonstrated that interactions, such as halogen bridges, play only a minor role outside the cavity. Understanding the importance of interactions for supramolecular hosts with guest molecules used for quartz microbalance analysis is essential for an improved design of affinity materials for this sensor application. Based on the results presented in this paper, we expect the development of further, more powerful affinity materials that can be used in quartz microbalance analysis. In the last part of this work, a new system for the detection, separation and storage of the environmentally harmful CFC trichlorofluoromethane was developed. In the study, planar Bragg grating sensors with per-methyl-, per-ethyl- and per-allyl-substituted cyclodextrins as affinity materials were sensitized to gaseous trichlorofluoromethane. This type of functionalization has proven to be highly efficient in its application, since a signal response up to 400 times higher than that of an identical but uncoated sensor could be achieved. The sensor device presented here has a detection limit of up to 5 ppm. A dependence of the adsorption kinetics on the substituent length could also be shown. On the one hand, the reaction times of the sensor decrease with increasing length of the substituents of the affinity material. On the other hand, a higher sensitivity could be observed with per-methylated cyclodextrins. In this way, a sensor system for trichlorofluoromethane detection could be realized and investigated. Particularly interesting results were obtained in connection of trichlorofluoromethane with per-methylated cyclodextrin. The ability of hexakis(2,3,6-tri-O-methyl)-α-cyclodextrin to selectively form a very stable supra-molecular complex with trichlorofluoromethane and thus store it permanently was demonstrated. The reversible complexation led to a highly efficient and stable crystallization in a ratio of 4:1, which was demonstrated both crystallographically and thermogravimetrically. Using the example of a binary mixture of dichloromethane and trichlorofluoromethane, the extraordinary selectivity of the Freon 11 complexation within the cyclodextrin cavity could be demonstrated. In addition, the applicability of hexakis(2,3,6-tri-O-methyl)-α-cyclodextrin as a packing material for fixed bed adsorption was demonstrated, enabling the production of economical, reusable and highly sustainable filter elements for gaseous trichlorofluoromethane. Furthermore, it could be shown that when this cyclodextrin was applied as an affinity layer on planar Bragg grating sensors, CFC-11 concentrations above 35 vol% led to a visible spontaneous crystallization of the per-Me cyclodextrin affinity layer on the sensor surface, so that this behavior can be effectively adapted as a disposable sensor and thus be used, for example, for monitoring industrial production plants or refrigerator disposal plants in order to protect the environment from exposure to the harmful trichlorofluoromethane

Understanding the burden of idiopathic generalized epilepsy in the United States, Europe, and Brazil: An analysis from the National Health and Wellness Survey.

The aim of this study was to understand the current burden of primary generalized tonic-clonic seizures (PGTCS) associated with idiopathic generalized epilepsy (IGE) as a function of seizure frequency. We analyzed data for (IGE) as a proxy measure of PGTCS. Little is known about the quality of life (QoL), health utility, productivity, healthcare resource utilization (HRU), and cost burden of PGTCS or IGE. Patients were identified from the US (2011, 2012, & 2013), 5EU (2011 & 2013), and Brazil (2011 & 2012) National Health and Wellness Survey, a nationally representative, internet-based survey of adults (18+ years). Patients that self-reported a diagnosis of IGE were categorized into seizure frequencies of: ≥1 seizure per week, 1-3 seizures per month, 1-4 seizures per year, or <1 seizure per year. QoL was measured using the SF-36v2 Mental (MCS) and Physical Component Summary (PCS) scores, health utilities with the SF-6D, productivity with the Work Productivity and Activity Impairment (WPAI) questionnaire, and HRU as reported in the past six months. Unit costs were estimated from the literature and multiplied against HRU values to calculate direct costs and WPAI values to calculate indirect costs. Generalized linear regression was utilized to examine the relationship between seizure frequency and each measure of burden with adjustment for covariates. Out of the general population surveyed, IGE was self-reported in 782 of 176,093 (US), 172 of 30,000 (UK), 106 of 30,001 (Germany), 87 of 30,000 (France), 31 of 12,011 (Spain), 22 of 17,500 (Italy), and 34 of 24,000 (Brazil). Persistent seizures (≥1 per year) were reported in over 40% of patients with IGE (10-15% with ≥1 seizure per week, 10-15% with 1-3 seizures per month, 20-25% with 1-4 seizures per year). Over 75% were treated with antiepileptic drugs (AEDs). Compared with those having <1 seizure per year (reference group), patients in the two most frequent seizure categories reported worse MCS and PCS scores. Patients in the three highest seizure frequency groups consistently reported worse health utility scores, and greater presenteeism (attending work while not physically or mentally capable of working), overall work impairment, activity impairment, HRU, indirect costs, and direct costs than the reference group. Despite the availability of AEDs during the year surveyed, a substantial number of patients experienced persistent seizures. Increasing seizure frequency was clearly associated with worse outcomes. The burden of PGTCS and IGE may be proportionally reduced by newer AEDs which may increase the proportion of seizure-free patients or shift more patients into lower seizure frequency categories

Intensive Care Admission and Early Neuro-Rehabilitation. Lessons for COVID-19?

Coronavirus disease 2019 (COVID-19) requires admission to intensive care (ICU) for the management of acute respiratory distress syndrome in about 5% of cases. Although our understanding of COVID-19 is still incomplete, a growing body of evidence is indicating potential direct deleterious effects on the central and peripheral nervous systems. Indeed, complex and long-lasting physical, cognitive, and functional impairments have often been observed after COVID-19. Early (defined as during and immediately after ICU discharge) rehabilitative interventions are fundamental for reducing the neurological burden of a disease that already heavily affects lung function with pulmonary fibrosis as a possible long-term consequence. In addition, ameliorating neuromuscular weakness with early rehabilitation would improve the efficiency of respiratory function as respiratory muscle atrophy worsens lung capacity. This review briefly summarizes the polymorphic burden of COVID-19 and addresses possible early interventions that could minimize the neurological and systemic impact. In fact, the benefits of early multidisciplinary rehabilitation after an ICU stay have been shown to be advantageous in several clinical conditions making an early rehabilitative approach generalizable and desirable to physicians from a wide range of different specialties