Interdisziplinäre Diagnostik und Therapie bei Patientinnen und Patienten mit ischämischem Schlaganfall und/ oder Vorhofflimmern

In der vorliegenden kumulativen Habilitationsschrift wurden eigene Arbeiten, die sich mit der Schlaganfallversorgung in Deutschland sowie mit VHF als Schlaganfall-Risikofaktor befassen, diskutiert. Die interdisziplinäre Kooperation verschiedener Fachrichtungen wie der Neurologie, Neuroradiologie, Kardiologie und Sportmedizin lagen dabei ebenfalls im Fokus und die vorgestellten Kooperationsprojekte sollen die Notwendigkeit einer engen Zusammenarbeit zur Optimierung der Patientenversorgung unterstreichen. Im Rahmen der berichteten Arbeiten konnten wir zeigen, dass intra-hospitale Therapiezeiten wie die DTG-Zeit insbesondere bei Patienten, die direkt in Thrombektomiezentren eingeliefert werden, einen relevanten Einfluss auf das funktionelle Ergebnis nach einem Schlaganfall haben. Diese Therapiezeiten sind eine beeinflussbare Größe in der Schlaganfallversorgung, deren Optimierung perspektivisch eine weitere Verbesserung der Prognose von Schlaganfallpatienten ermöglichen kann. Ein besonderer Fokus sollte dabei nach unseren Ergebnissen auf den zeitlichen Abläufen während personell schwach besetzter Zeiten (am Wochenende und nachts) wie auch bei der Lysetherapie liegen. Hier ist eine gute Zusammenarbeit von Neurologen und Neuroradiologen von Nöten. In einer neurologisch-kardiologischen Kooperation konnten wir zeigen, dass die Prävalenz von klinisch stummen zerebralen Ischämien bei VHF-Patienten mit und ohne weitere kardiovaskuläre Risikofaktoren vergleichbar sind. Weitere Studien sind erforderlich um zu untersuchen, ob diese klinisch stummen zerebralen Ischämien in der Entscheidungsfindung zur medikamentösen Schlaganfallprophylaxe den klinisch manifesten Schlaganfällen gleichzusetzen sind. Ebenfalls eine neurologisch-kardiologische Gemeinschaftsarbeit war die MACPAF-Studie. Das hier vorgestellte wesentliche Ergebnis dieser Studie war die verhältnismäßig hohe VHF-Detektionsrate innerhalb eines Jahres nach einer einmaligen Pulmonalvenenisolation unter Verwendung eines implantierten EKG-Rekorders. Auch konnten wir berichten, dass weder VHF-Rezidive per se noch die VHF-Last einen signifikanten Einfluss auf die neurokognitive Funktion hatten. Im Rahmen der Berlin beat of running study beobachten wir gemeinsam mit Sportmedizinern und Kardiologen eine niedrige Rate von VHF während eines Marathonlaufes. Wir fanden jedoch eine verhältnismäßig hohe Anzahl von anderen EKG-Veränderungen wie ventrikuläre Tachykardien und ST-T-Streckenveränderungen, die gemeinsam mit hsTnT-Erhöhungen für eine relevante kardiale Stressreaktion insbesondere bei älteren Marathonläufern sprechen. Diese könnten ebenso wie erhöhte Marker endothelialer Schädigung Teil eines pathophysiologischen Modells für kardiale Umbauprozesse mit nachfolgend erhöhtem Risiko für VHF sein. Dieselben oder ähnliche Mechanismen könnten für die ebenfalls beobachtete singuläre zerebrale akut-ischämische Läsion in zeitlicher Nähe zu dem Marathonlauf verantwortlich sein. Mit den vorgestellten Arbeiten dieser Habilitationsschrift können Risikogruppen für die ischämische Schlaganfälle und VHF besser identifiziert werden, um eine individuelle (medikamentöse) Prävention zu ermöglichen. Zudem können Patienten genauer über die Risiken und Chancen von Katheterablationen wie auch über die Risiken von hochintensiven sportlichen Aktivitäten wie Marathonläufen aufgeklärt werden. Mit der DTG-Zeit wurde eine beinflussbare Größe in der Behandlung von Schlaganfallpatienten aufgezeigt und konkrete Ansätze benannt um das funktionelle Ergebnis nach Schlaganfällen zu optimieren. Die vorgestellten Arbeiten sind zudem Grundlage für zukünftige wissenschaftliche Untersuchungen

Impact of chronic inflammatory airway disease on stroke severity and long-term survival after ischemic stroke - a retrospective analysis

Background Chronic inflammatory airway disease (CIAD) has emerged as independent risk factor for cardiovascular mortality and ischemic stroke but the impact of co-existing CIAD in patients with ischemic stroke is less clear. Methods We retrospectively analyzed 1013 patients with acute ischemic stroke who were consecutively admitted to the Department of Neurology, Charité - Universitätsmedizin Berlin, Germany within one year. Mean follow-up was 80 months (IQR 32–85 months). Using multivariable regression models we analyzed the impact of CIAD (defined as chronic obstructive pulmonary disease or asthma bronchiale) on stroke severity and outcome. Results Co-existing CIAD was evident in 7.1 % (n = 72) of all patients with acute ischemic stroke. Baseline characteristics of stroke patients with CIAD did not differ significantly from ischemic stroke patients without CIAD. Age (OR 1.17 [95 % CI 1.03-1.37] per decade), atrial fibrillation (OR 3.43 [95 % CI 2.47-4.78]) and coronary artery disease (OR 1.51 [95 % CI 1.07–2.14]) but not a history of CIAD (p = 0.30) were associated with severe stroke (NIHSS≥11) on hospital admission. Age (HR 1.70 [95 % CI 1.53-1.87] per decade), peripheral artery disease (HR 1.91 [95 % CI 1.35-2.7]), stroke severity at hospital admission (NIHSS per point HR 1.08 [95 % CI 1.06-1.10]), and history of CIAD (HR 1.43 [95 % CI 1.02-2.00]) were independently associated with mortality during long-term follow-up. However, CIAD was not significantly associated with short-term mortality after stroke. Conclusion Co-existing CIAD showed no significant association with stroke severity at hospital admission and early mortality after ischemic stroke. CIAD was negatively associated with long-term survival after ischemic stroke

Heart Rate Variability and Recurrent Stroke and Myocardial Infarction in Patients With Acute Mild to Moderate Stroke

Objectives: In patients with acute ischemic stroke, reduced heart rate variability (HRV) may indicate poor outcome. We tested whether HRV in the acute phase of stroke is associated with higher rates of mortality, recurrent stroke, myocardial infarction (MI) or functional outcome. Materials and Methods: Patients with acute mild to moderate ischemic stroke without known atrial fibrillation were prospectively enrolled to the investigator-initiated Heart and Brain interfaces in Acute Ischemic Stroke (HEBRAS) study (NCT 02142413). HRV parameters were assessed during the in-hospital stay using a 10-min section of each patient's ECG recording at day- and nighttime, calculating time and frequency domain HRV parameters. Frequency of a combined endpoint of recurrent stroke, MI or death of any cause and the respective individual events were assessed 12 months after the index stroke. Patients' functional outcome was measured by the modified Rankin Scale (mRS) at 12 months. Results: We included 308 patients (37% female, median NIHSS = 2 on admission, median age 69 years). Complete follow-up was achieved in 286/308 (93%) patients. At 12 months, 32 (9.5%), 5 (1.7%) and 13 (3.7%) patients had suffered a recurrent stroke, MI or death, respectively. After adjustment for age, sex, stroke severity and vascular risk factors, there was no significant association between HRV and recurrent stroke, MI, death or the combined endpoint. We did not find a significant impact of HRV on a mRS ≥ 2 12 months after the index stroke. Conclusion: HRV did not predict recurrent vascular events in patients with acute mild to moderate ischemic stroke

results of the prospective observational Berlin Beat of Running study

Objectives: While regular physical exercise has many health benefits, strenuous physical exercise may have a negative impact on cardiac function. The ‘Berlin Beat of Running’ study focused on feasibility and diagnostic value of continuous ECG monitoring in recreational endurance athletes during a marathon race. We hypothesised that cardiac arrhythmias and especially atrial fibrillation are frequently found in a cohort of recreational endurance athletes. The main secondary hypothesis was that pathological laboratory findings in these athletes are (in part) associated with cardiac arrhythmias. Design: Prospective observational cohort study including healthy volunteers. Setting and participants: One hundred and nine experienced marathon runners wore a portable ECG recorder during a marathon race in Berlin, Germany. Athletes underwent blood tests 2–3 days prior, directly after and 1–2 days after the race. Results: Overall, 108 athletes (median 48 years (IQR 45–53), 24% women) completed the marathon in 249±43 min. Blinded ECG analysis revealed abnormal findings during the marathon in 18 (16.8%) athletes. Ten (9.3%) athletes had at least one episode of non-sustained ventricular tachycardia, one of whom had atrial fibrillation; eight (7.5%) individuals showed transient ST-T-segment deviations. Abnormal ECG findings were associated with advanced age (OR 1.11 per year, 95% CI 1.01 to 1.23), while sex and cardiovascular risk profile had no impact. Directly after the race, high-sensitive troponin T was elevated in 18 (16.7%) athletes and associated with ST-T-segment deviation (OR 9.9, 95% CI 1.9 to 51.5), while age, sex and cardiovascular risk profile had no impact. Conclusions: ECG monitoring during a marathon is feasible. Abnormal ECG findings were present in every sixth athlete. Exercise-induced transient ST-T-segment deviations were associated with elevated high-sensitive troponin T (hsTnT) values. Trial registration: ClinicalTrials.gov NCT01428778; Results

MRI-detected brain lesions in AF patients without further stroke risk factors undergoing ablation - a retrospective analysis of prospective studies

Abstract Background Atrial fibrillation (AF) without other stroke risk factors is assumed to have a low annual stroke risk comparable to patients without AF. Therefore, current clinical guidelines do not recommend oral anticoagulation for stroke prevention of AF in patients without stroke risk factors. We analyzed brain magnetic resonance imaging (MRI) imaging to estimate the rate of clinically inapparent (“silent”) ischemic brain lesions in these patients. Methods We pooled individual patient-level data from three prospective studies comprising stroke-free patients with symptomatic AF. All study patients underwent brain MRI within 24–48 h before planned left atrial catheter ablation. MRIs were analyzed by a neuroradiologist blinded to clinical data. Results In total, 175 patients (median age 60 (IQR 54–67) years, 32% female, median CHA2DS2-VASc = 1 (IQR 0–2), 33% persistent AF) were included. In AF patients without or with at least one stroke risk factor, at least one silent ischemic brain lesion was observed in 4 (8%) out of 48 and 10 (8%) out of 127 patients, respectively (p > 0.99). Presence of silent ischemic brain lesions was related to age (p = 0.03) but not to AF pattern (p = 0.77). At least one cerebral microbleed was detected in 5 (13%) out of 30 AF patients without stroke risk factors and 25 (25%) out of 108 AF patients with stroke risk factors (p = 0.2). Presence of cerebral microbleeds was related to male sex (p = 0.04) or peripheral artery occlusive disease (p = 0.03). Conclusion In patients with symptomatic AF scheduled for ablation, brain MRI detected silent ischemic brain lesions in approximately one in 12 patients, and microbleeds in one in 5 patients. The prevalence of silent ischemic brain lesions did not differ in AF patients with or without further stroke risk factors

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

results of a prospective monocentric randomised study

Einleitung: Die linksatriale Pulmonalvenenisolation (PVI) ist eine etablierte therapeu-tische Option bei symptomatischem Vorhofflimmern (VHF). Akute zerebrale Ischä-mien sind eine bekannte Komplikation der PVI und treten bei etwa 0,5-1% aller Pati-enten auf. Darüber hinaus treten bei bis zu 39% aller Patienten mittels Magnetreso-nanztomographie (MRT) detektierbare zerebrale Ischämien ohne konsekutive neuro-logische Defizite auf, deren klinische Relevanz bislang nicht abschließend geklärt ist. Methodik: In die prospektive monozentrische Studie „Mesh Ablator versus Cryobal-loon Pulmonary Vein Ablation of Symptomatic Paroxysmal Atrial Fibrillation“ (MAC-PAF) wurden bis zum vorzeitigen Abbruch der Studie 44 Patienten mit symptomati-schem paroxysmalen VHF eingeschlossen. Diese wurden 1:1 für eine PVI unter Verwendung des HD Mesh Ablator® oder des Arctic Front® Katheters randomisiert. Eine zerebrale MRT bei 3 Tesla, eine neurologische Untersuchung und eine neuro-psychologische Testung erfolgten vor und innerhalb von 48 Stunden nach PVI, sowie nach sechs Monaten. Primärer Endpunkt war das Erreichen einer vollständigen PVI gemessen am Erregungsleitungsblock (EB) aller Pulmonalvenen (PV). Sekundäre Endpunkte waren das Auftreten zerebraler Ischämien und deren neu-ro(psycho)logische Folgen. Ergebnisse: Es erfolgten 41 Ablationen bei 37 der 44 eingeschlossenen Patienten, die im Median 63 Jahre alt, zu 43% weiblich waren und einen medianen CHA2DS2-VASc Score von 2 aufwiesen. Im Rahmen der Intention-to-treat-Analyse bestand ein vollständiger EB bei 9,5% der HD Mesh Ablator® randomisierten Patienten, sowie bei 56,5% der Arctic Front® randomisierten Patienten (p=0,001). Im unmittelbar post-interventionell durchgeführten MRT fanden sich 56 akute zerebrale Läsionen bei 16 (43%) aller 37 Patienten, ohne dass fokal-neurologische oder neuropsychologische Defizite nachgewiesen werden konnten. Sechs Monate nach erfolgter PVI waren le-diglich sieben (12,5%) dieser Läsionen als zerebrale Gliose in 5 (31,3%) der 16 Pati- enten nachweisbar. Auch bei persistierenden zerebralen Läsionen ließ sich kein neu-ro(psycho)logisches Defizit aufzeigen. Schlussfolgerung: Im Rahmen der prospektiven randomisierten MACPAF-Studie zeigte sich der Arctic Front® Katheter dem HD Mesh Ablator® Katheter im Hinblick auf das Erreichen einer vollständigen PVI aller PV überlegen. Postinterventionell fanden sich im MRT bei 43% aller Patienten zumindest eine akute zerebrale Läsion. Auch wenn jede achte zerebrale Läsion nach sechs Monaten eine Gliose verursach-te, konnten keine signifikanten neurokognitiven Defizite nachgewiesen werden.Introduction: Pulmonary vein isolation (PVI) is an established therapeutic approach in symptomatic atrial fibrillation (AF). Acute cerebral ischemia is a known complica-tion and occurs in about 0.5-1% of all patients. Furthermore, magnetic resonance imaging (MRI) has detected cerebral ischemia without consecutive neurological defi-cits in up to 39% of all patients. The clinical relevance of these brain lesions is fully understood. Method: According to the protocol of the prospective monocentric study „Mesh Abla-tor versus Cryoballoon Pulmonary Vein Ablation of Symptomatic Paroxysmal Atrial Fibrillation“ (MACPAF), patients with symptomatic paroxysmal AF were randomized 1:1 to PVI using the HD Mesh Ablator® or the Arctic Front® catheter. Until premature study termination, 44 patients were included. Cerebral 3 Tesla MRI, neurological ex-amination and neuropsychological testing were performed before and within 48 hours after PVI, as well as after six months. The primary endpoint was achieving complete PVI, verified by an exit- block (EB) of all pulmonary veins (PV). Secondary endpoints were the incidence of cerebral ischemia and their neuro(psycho)logical impact. Results: We performed 41 ablations in 37 of 44 randomized patients. Median age was 63 years, 43% were female and median CHA2DS2-VASc score was 2. According to intention-to-treat analysis, complete EB was achieved in 9.5% of all patients ran-domized to the HD Mesh Ablator®, and in 56.5% of all patients randomized to the Arctic Front® catheter (p=0.001). MRI immediately after PVI showed 56 acute cere-bral lesions in 16 (43%) of all 37 patients while no neurological or neurocognitive def-icits could be detected. After six months, seven (13%) of these acute brain lesions could be detected as cerebral gliosis in 5 (31%) of 16 patients. However, persisting brain lesions had no effect on cognitive performance. Conclusion: The MACPAF study revealed superiority of the Arctic Front® catheter over the HD Mesh Ablator® catheter concerning complete PVI of all PV. According to post-procedural 3T MRI, at least one ischemic brain lesion was found in 43% of all patients. While every eighth cerebral lesion formed a glial scar after six months, this was not associated with a significantly impaired cognitive function

Rate of cardiac arrhythmias and silent brain lesions in experienced marathon runners: rationale, design and baseline data of the Berlin Beat of Running study

Abstract Background Regular exercise is beneficial for cardiovascular health but a recent meta-analysis indicated a relationship between extensive endurance sport and a higher risk of atrial fibrillation, an independent risk factor for stroke. However, data on the frequency of cardiac arrhythmias or (clinically silent) brain lesions during and after marathon running are missing. Methods/ Design In the prospective observational “Berlin Beat of Running” study experienced endurance athletes underwent clinical examination (CE), 3 Tesla brain magnetic resonance imaging (MRI), carotid ultrasound imaging (CUI) and serial blood sampling (BS) within 2-3 days prior (CE, MRI, CUI, BS), directly after (CE, BS) and within 2 days after (CE, MRI, BS) the 38th BMW BERLIN-MARATHON 2011. All participants wore a portable electrocardiogram (ECG)-recorder throughout the 4 to 5 days baseline study period. Participants with pathological MRI findings after the marathon, troponin elevations or detected cardiac arrhythmias will be asked to undergo cardiac MRI to rule out structural abnormalities. A follow-up is scheduled after one year. Results Here we report the baseline data of the enrolled 110 athletes aged 36-61 years. Their mean age was 48.8 ± 6.0 years, 24.5% were female, 8.2% had hypertension and 2.7% had hyperlipidaemia. Participants have attended a mean of 7.5 ± 6.6 marathon races within the last 5 years and a mean of 16 ± 36 marathon races in total. Their weekly running distance prior to the 38th BMW BERLIN-MARATHON was 65 ± 17 km. Finally, 108 (98.2%) Berlin Beat-Study participants successfully completed the 38th BMW BERLIN-MARATHON 2011. Discussion Findings from the “Berlin Beats of Running” study will help to balance the benefits and risks of extensive endurance sport. ECG-recording during the marathon might contribute to identify athletes at risk for cardiovascular events. MRI results will give new insights into the link between physical stress and brain damage. Trial registration clinicaltrials.gov NCT01428778</p

Rate of cardiac arrhythmias and silent brain lesions in experienced marathon runners: rationale, design and baseline data of the Berlin Beat of Running study

Background: Regular exercise is beneficial for cardiovascular health but a recent meta-analysis indicated a relationship between extensive endurance sport and a higher risk of atrial fibrillation, an independent risk factor for stroke. However, data on the frequency of cardiac arrhythmias or (clinically silent) brain lesions during and after marathon running are missing. Methods/Design: In the prospective observational "Berlin Beat of Running" study experienced endurance athletes underwent clinical examination (CE), 3 Tesla brain magnetic resonance imaging (MRI), carotid ultrasound imaging (CUI) and serial blood sampling (BS) within 2-3 days prior (CE, MRI, CUI, BS), directly after (CE, BS) and within 2 days after (CE, MRI, BS) the 38$^{th}$ BMW BERLIN-MARATHON 2011. All participants wore a portable electrocardiogram (ECG)-recorder throughout the 4 to 5 days baseline study period. Participants with pathological MRI findings after the marathon, troponin elevations or detected cardiac arrhythmias will be asked to undergo cardiac MRI to rule out structural abnormalities. A follow-up is scheduled after one year. Results: Here we report the baseline data of the enrolled 110 athletes aged 36-61 years. Their mean age was 48.8 $\pm$ 6.0 years, 24.5% were female, 8.2% had hypertension and 2.7% had hyperlipidaemia. Participants have attended a mean of 7.5 $\pm$ 6.6 marathon races within the last 5 years and a mean of 16 $\pm$ 36 marathon races in total. Their weekly running distance prior to the 38$^{th}$ BMW BERLIN-MARATHON was 65 $\pm$ 17 km. Finally, 108 (98.2%) Berlin Beat-Study participants successfully completed the 38$^{th}$ BMW BERLIN-MARATHON 2011. Discussion: Findings from the "Berlin Beats of Running" study will help to balance the benefits and risks of extensive endurance sport. ECG-recording during the marathon might contribute to identify athletes at risk for cardiovascular events. MRI results will give new insights into the link between physical stress and brain damage