Individualised prediction of drug resistance and seizure recurrence after medication withdrawal in people with juvenile myoclonic epilepsy: A systematic review and individual participant data meta-analysis

Summary Background A third of people with juvenile myoclonic epilepsy (JME) are drug-resistant. Three-quarters have a seizure relapse when attempting to withdraw anti-seizure medication (ASM) after achieving seizure-freedom. It is currently impossible to predict who is likely to become drug-resistant and safely withdraw treatment. We aimed to identify predictors of drug resistance and seizure recurrence to allow for individualised prediction of treatment outcomes in people with JME. Methods We performed an individual participant data (IPD) meta-analysis based on a systematic search in EMBASE and PubMed – last updated on March 11, 2021 – including prospective and retrospective observational studies reporting on treatment outcomes of people diagnosed with JME and available seizure outcome data after a minimum one-year follow-up. We invited authors to share standardised IPD to identify predictors of drug resistance using multivariable logistic regression. We excluded pseudo-resistant individuals. A subset who attempted to withdraw ASM was included in a multivariable proportional hazards analysis on seizure recurrence after ASM withdrawal. The study was registered at the Open Science Framework (OSF; https://osf.io/b9zjc/). Findings  368) was predicted by an earlier age at the start of withdrawal, shorter seizure-free interval and more currently used ASMs, resulting in an average internal-external cross-validation concordance-statistic of 0·70 (95%CI 0·68–0·73). Interpretation We were able to predict and validate clinically relevant personalised treatment outcomes for people with JME. Individualised predictions are accessible as nomograms and web-based tools. Funding MING fonds

regulation of endothelial phenotype by shear stress

Das Endothel, eine einschichtige Zelldecke, ist als innerste Auskleidung von Blutgefäßen direkt dem strömenden Blut ausgesetzt. Sein Funktionszustand wird neben anderen biochemischen und mechanischen Einflüssen durch Wandschubspannung moduliert. Diese ist je nach Lokalisation im Gefäßnetz unterschiedlich: an Prädilektionsstellen für Atherosklerose herrschen andere Strömungsverhältnisse als in davor geschützten Gefäßabschnitten, sprossende Kapillaren wiederum werden gar nicht perfundiert. Untersucht wurde die schubspannungsabhängige Regulation dreier phänotypisch bedeutsamer Proteine: Connexin-40 (Cx40) verbindet Endothelzellen als Kommunikationsprotein und ist wichtig für koordinierte Gefäßerweiterung, Hyaluronsäuresynthetase- 2 (HAS2) bildet Hyaluronan, einen essentiellen Bestandteil der endothelialen Oberflächenschicht, und ADAMTS1 hemmt Gefäßneubildung. In vitro induzierte Beströmung mRNA und Protein von Cx40, HAS2 und ADAMTS1 in jeweils spezifischen Zeitverläufen. Das Expressionsmaximum von Cx40 und HAS2 lag bei mittleren Schubspannungsstärken um 6 dyn / cm², ADAMTS1 hingegen war umso stärker exprimiert, je stärker die Strömung war. Pulsatile, typisch atheroprotektive Beströmung hatte den vergleichbar stärksten Effekt, ganz im Gegensatz zu einem typisch atherogenen Flussprofil. In den meisten untersuchten Konstellationen war zwar die Grundexpression von der Aktivität der PI3-Kinase abhängig, nicht aber die strömungsabhängige Induktion, obwohl PI3-Kinase durch Schubspannung aktiviert wird. Im Rattenmesenterium wurde gezeigt, dass ADAMTS1 in perfundierten Gefäßen hoch exprimiert wird, in sprossenden Kapillaren hingegen supprimiert. Zudem konnte Strömung in vitro analog zur Induktion von HAS2 auch die Synthese von Hyaluronan steigern. Ein Transfer der schubspannungsabhängigen Regulationscharakteristik von Cx40 in computersimulierte Gefäßnetzwerke führte in letzteren zu realitätsnäherer Adaptation. In den drei vorgelegten Publikationen wurde insgesamt nicht nur der Einfluss von Schubspannung definierter Art, Stärke und Dauer auf die Expression von Cx40, HAS2 und ADAMTS1 detailliert analysiert, sondern es konnten auch funktionelle Konsequenzen und damit eine strömungsabhängige Regulation des endothelialen Phänotyps dargestellt werden.The endothelial monolayer as the innermost lining of blood vessels is directly exposed to the flowing blood. Besides several other biochemical and mechanical factors, wall shear stress modulates the endothelial function. The concrete pattern of shear stress depends on the localization within the vascular network: flow profiles in predilection sites for atherosclerosis differ from those in vessel segments protected from atherosclerosis; sprouting capillaries instead are not perfused at all. The goal of the three studies presented here was to analyze the shear stress dependent regulation of three important endothelial proteins: Connexin-40 (Cx40) as a communication protein connects endothelial cells and facilitates the upstream conduction of vasodilatory signals. Hyaluronan synthase 2 (HAS2) produces hyaluronan, an essential component of the endothelial surface layer. ADAMTS1 again inhibits angiogenesis. In vitro, flow induced mRNA and protein expression of Cx40, HAS2 and ADAMTS1, each following specific time courses. Maximal expression of Cx40 and HAS2 was found at moderate shear stress levels around 6 dyn / cm² whereas ADAMTS1 expression was proportional to flow levels. Pulsatile atheroprotective flow had the most marked effect in contrast to a atherogenic flow profile. In most cases, basic expression but not flow dependent induction was depending on PI3 kinase activity although PI3 kinase is known to be activated by shear stress. In a rat mesentery network, ADAMTS1 was highly expressed in perfused vessels but suppressed in sprouting capillaries. In vitro, flow induced not only HAS2 but also synthesis of hyaluronan. A transfer of the flow dependent Cx40 regulation mechanism into a computer model of a microvascular network led to more realistic adaptation. In the three studies presented here, not only the influence of shear stress of defined pattern, force and time on Cx40, HAS2 and ADAMTS1 expression was analyzed in detail but also functional consequences and therefore a flow mediated regulation of the endothelial phenotype could be demonstrated

Expression of ADAMTS1 in endothelial cells is induced by shear stress and suppressed in sprouting capillaries

ADAMTS1 inhibits capillary sprouting, and since capillary sprouts do not experience the shear stress caused by blood flow, this study undertook to clarify the relationship between shear stress and ADAMTS1. It was found that endothelial cells exposed to shear stress displayed a strong upregulation of ADAMTS1, dependent upon both the magnitude and duration of their exposure. Investigation of the underlying pathways demonstrated involvement of phospholipase C, phosphoinositide 3-kinase, and nitric oxide. Forkhead box protein O1 was identified as a likely inhibitor of the system, as its knockdown was followed by a slight increase in ADAMTS1 expression. In silico prediction displayed a transcriptional binding site for Forkhead box protein O1 in the promotor region of the ADAMTS1 gene, as well as sites for nuclear factor 1, SP1, and AP-1. The anti-angiogenic effects of ADAMTS1 were attributed to its cleavage of thrombospondin 1 into a 70-kDa fragment, and a significant enhancement of this fragment was indeed demonstrated by immunoblotting shear stress-treated cells. Accordingly, scratch wound closure displayed a slowdown in conditioned medium from shear stress-treated endothelial cells, an effect that could be completely blocked by a knockdown of thrombospondin 1 and partially blocked by a knockdown of ADAMTS1. Non-perfused capillary sprouts in rat mesenteries stained negative for ADAMTS1, while vessels in the microcirculation that had already experienced blood flow yielded the opposite results. The shear stress-dependent expression of ADAMTS1 in vitro was therefore also demonstrated in vivo and thereby confirmed as a mechanism connecting blood flow with the regulation of angiogenesis

Prognosis and management of acute symptomatic seizures: a prospective, multicenter, observational study

Abstract Background Acute symptomatic epileptic seizures are frequently seen in neurocritical care. To prevent subsequent unprovoked seizures, long-term treatments with antiseizure medications are often initiated although supporting evidence is lacking. This study aimed at prospectively assessing the risk of unprovoked seizure relapse with respect to the use of antiseizure medications. It was hypothesized that after a first acute symptomatic seizure of structural etiology, the cumulative 12-month risk of unprovoked seizure relapse is ≤ 25%. Methods Inclusion criteria were age ≥ 18 and acute symptomatic first-ever epileptic seizure; patients with status epilepticus were excluded. Using telephone and mail interviews, participants were followed for 12 months after the acute symptomatic first seizure. Primary endpoint was the occurrence and timing of a first unprovoked seizure relapse. In addition, neuro-intensivists in Germany were interviewed about their antiseizure treatment strategies through an anonymous online survey. Results Eleven of 122 participants with structural etiology had an unprovoked seizure relapse, resulting in a cumulative 12-month risk of 10.7% (95%CI, 4.7%–16.7%). None of 19 participants with a non-structural etiology had a subsequent unprovoked seizure. Compared to structural etiology alone, combined infectious and structural etiology was independently associated with unprovoked seizure relapse (OR 11.1; 95%CI, 1.8–69.7). Median duration of antiseizure treatment was 3.4 months (IQR 0–9.3). Seven out of 11 participants had their unprovoked seizure relapse while taking antiseizure medication; longer treatment durations were not associated with decreased risk of unprovoked seizure relapse. Following the non-representative online survey, most neuro-intensivists consider 3 months or less of antiseizure medication to be adequate. Conclusions Even in case of structural etiology, acute symptomatic seizures bear a low risk of subsequent unprovoked seizures. There is still no evidence favoring long-term treatments with antiseizure medications. Hence, individual constellations with an increased risk of unprovoked seizure relapse should be identified, such as central nervous system infections causing structural brain damage. However, in the absence of high-risk features, antiseizure medications should be discontinued early to avoid overtreatment

Individualised prediction of drug resistance and seizure recurrence after medication withdrawal in people with juvenile myoclonic epilepsy: A systematic review and individual participant data meta-analysis

Background A third of people with juvenile myoclonic epilepsy (JME) are drug-resistant. Three-quarters have a seizure relapse when attempting to withdraw anti-seizure medication (ASM) after achieving seizure-freedom. It is currently impossible to predict who is likely to become drug-resistant and safely withdraw treatment. We aimed to identify predictors of drug resistance and seizure recurrence to allow for individualised prediction of treatment outcomes in people with JME. Methods We performed an individual participant data (IPD) meta-analysis based on a systematic search in EMBASE and PubMed – last updated on March 11, 2021 – including prospective and retrospective observational studies reporting on treatment outcomes of people diagnosed with JME and available seizure outcome data after a minimum one-year follow-up. We invited authors to share standardised IPD to identify predictors of drug resistance using multivariable logistic regression. We excluded pseudo-resistant individuals. A subset who attempted to withdraw ASM was included in a multivariable proportional hazards analysis on seizure recurrence after ASM withdrawal. The study was registered at the Open Science Framework (OSF; https://osf.io/b9zjc/). Findings Our search yielded 1641 articles; 53 were eligible, of which the authors of 24 studies agreed to collaborate by sharing IPD. Using data from 2518 people with JME, we found nine independent predictors of drug resistance: three seizure types, psychiatric comorbidities, catamenial epilepsy, epileptiform focality, ethnicity, history of CAE, family history of epilepsy, status epilepticus, and febrile seizures. Internal-external cross-validation of our multivariable model showed an area under the receiver operating characteristic curve of 0·70 (95%CI 0·68–0·72). Recurrence of seizures after ASM withdrawal (n = 368) was predicted by an earlier age at the start of withdrawal, shorter seizure-free interval and more currently used ASMs, resulting in an average internal-external cross-validation concordance-statistic of 0·70 (95%CI 0·68–0·73). Interpretation We were able to predict and validate clinically relevant personalised treatment outcomes for people with JME. Individualised predictions are accessible as nomograms and web-based tools