Pathophysiologie und Behandlung der Blutungsexpansion bei akuten intrazerebralen Blutungen

Die intrazerebrale Blutung ist der Subtyp des Schlaganfalls mit der höchsten Mortalität und eine Verbesserung der Behandlungsoptionen ist dringend erforderlich. Mit dieser Arbeit soll ein Beitrag geleistet werden, um die Pathophysiologie der Blutungsexpansion besser zu verstehen und neue Behandlungsansätze im Falle einer intrazerebralen Blutung, insbesondere unter Antikoagulation, zu untersuchen. Es wurde ein neues experimentelles Mausmodell entwickelt um den Mechanismus des Blutungswachstums besser zu verstehen. Hierbei konnte zum ersten Mal Fishers „Avalanche-Theorie“ bestätigt und die Gesetzmäßigkeiten dahinter näher beleuchtet werden. Neben rein mechanischen Gesichtspunkten wurde dabei auch der Einfluss von Antikoagulation und Blutdruck in einer spezifischen Phase des Blutungswachstums, nämlich nach sekundär mechanischem Zerreißen von zerebralen Blutgefäßen, untersucht. Der Einfluss der Blutdruckhöhe auf die Blutungsexpansion vor dem Hintergrund einer Antikoagulation mit Warfarin wurde von uns auch in einer klinischen Studie an 69 antikoagulierten Patienten und 69 nicht antikoagulierten Kontrollpatienten, retrospektiv untersucht. Im Gegensatz zu einzelnen anderen Publikationen fanden wir keinen Zusammenhang zwischen dem Blutdruck in den ersten 24 Stunden und der Blutungsexpansion. Möglicherweise hat die Blutdruckhöhe in den verschiedenen Phasen der Blutungsexpansion unterschiedliche Auswirkungen was diskrepante Ergebnisse zu anderen Gruppen erklären mag. In einer weiteren Arbeit wurde anhand der Daten einer großen randomisierten klinischen Studie (ATACH-2 umfasste 1000 Patienten) mit einer im Voraus geplanten Subgruppenanalyse untersucht, ob eine Erkrankung der kleinen zerebralen Gefäße, welche ihren Ausdruck in zerebralen Mikroblutungen findet, assoziiert ist mit einem erhöhten Risiko der Blutungsexpansion. Während sich eine hohe Prävalenz zerebraler Mikroblutungen bei intrazerebralen Blutungen zeigte, konnte kein erhöhtes Risiko für Blutungsexpansion festgestellt werden. Mit der Zulassung von neuen oralen Antikoagulantien stellte sich die Frage nach deren Sicherheitsprofil. Experimentell konnten wir in zwei unterschiedlichen Mausmodellen (Collagenase-Modell, Lasermodell kortikaler Mikroblutungen) als erste einen Sicherheitsvorteil des direkten Thrombininhibitors Dabigatran im Vergleich zu einer herkömmlichen Antikoagulation mit dem Vitamin-K-Antagonisten Warfarin im Hinblick auf Blutungsgröße der intrazerebralen Blutung feststellen. Neben direkten praktischen Implikationen, wirft diese Arbeit auch ein Licht auf die Wichtigkeit und Komplexität der Gerinnungskaskade im Hinblick auf Blutungsexpansion. Diese Zusammenhänge untersuchten wir auch noch einmal eingehender, indem wir das etablierte Collagenase-Modell der intrazerebralen Blutung mit moderner kontrastmittelgestützter Dual-Energy Computertomographie verbanden und so experimentell zeigen konnten, dass Blutungen unter Dabigatran früher sistieren als unter Warfarin. Dieser Effekt konnte mit der Gabe von Prothrombinkomplex-Konzentrat bei Blutungen unter Warfarin aufgehoben werden. Die Effektivität von Prothrombinkomplex-Konzentrat im Hinblick auf eine Begrenzung des Blutungswachstums im Falle einer intrazerebralen Blutung konnten wir noch in einer weiteren Arbeit experimentell bestätigen. Zusätzlich gelang es uns darzulegen, dass rFVIIa äquivalent effektiv in der Lage ist, die Gerinnung rasch zu normalisieren und Blutungsexpansion zu verhindern. In einer letzten Arbeit setzten wir den Fokus auf die Behandlung von Sekundärschäden wie Blut-Hirn-Schrankenstörung und Hirnödem nach experimenteller intrazerebraler Blutung. Das immunmodulatorisch wirksame Medikament Fingolimod (FTY720) zeigte sich hier, anders als in einigen experimentellen Arbeiten zum ischämischen Schlaganfall, nicht neuroprotektiv wirksam. Zusammenfassend hat sich in den vergangenen Jahren die Forschung zur intrazerebralen Blutung intensiviert. Durch den technischen Fortschritt werden wir in Zukunft immer schneller zum Patienten und zur Diagnose gelangen. Damit sind wir vielleicht schon in absehbarer Zeit in der Lage, den Patienten in der mutmaßlich vulnerabelsten Phase seiner Erkrankung zu behandeln. Weitere Forschung ist notwendig, um die Pathophysiologie der intrazerebralen Blutung im Detail zu verstehen, Diagnosealgorithmen zu verbessern und Behandlungsoptionen, insbesondere zur Hämostase zu entwickeln

Volumetric accuracy of different imaging modalities in acute intracerebral hemorrhage

Background: Follow-up imaging in intracerebral hemorrhage is not standardized and radiologists rely on different imaging modalities to determine hematoma growth. This study assesses the volumetric accuracy of different imaging modalities (MRI, CT angiography, postcontrast CT) to measure hematoma size. Methods: 28 patients with acute spontaneous intracerebral hemorrhage referred to a tertiary stroke center were retrospectively included between 2018 and 2019. Inclusion criteria were (1) spontaneous intracerebral hemorrhage (supra- or infratentorial), (2) noncontrast CT imaging performed on admission, (3) follow-up imaging (CT angiography, postcontrast CT, MRI), and (4) absence of hematoma expansion confirmed by a third cranial image within 6 days. Two independent raters manually measured hematoma volume by drawing a region of interest on axial slices of admission noncontrast CT scans as well as on follow-up imaging (CT angiography, postcontrast CT, MRI) using a semi-automated segmentation tool (Visage image viewer; version 7.1.10). Results were compared using Bland-Altman plots. Results: Mean admission hematoma volume was 18.79 +/- 19.86 cc. All interrater and intrarater intraclass correlation coefficients were excellent (1; IQR 0.98-1.00). In comparison to hematoma volume on admission noncontrast CT volumetric measurements were most accurate in patients who received postcontrast CT (bias of - 2.47%, SD 4.67: n = 10), while CT angiography often underestimated hemorrhage volumes (bias of 31.91%, SD 45.54; n = 20). In MRI sequences intracerebral hemorrhage volumes were overestimated in T2* (bias of - 64.37%, SD 21.65; n = 10). FLAIR (bias of 6.05%, SD 35.45; n = 13) and DWI (bias of-14.6%, SD 31.93; n = 12) over- and underestimated hemorrhagic volumes. Conclusions: Volumetric measurements were most accurate in postcontrast CT while CT angiography and MRI sequences often substantially over- or underestimated hemorrhage volumes

Intravenous tPA therapy does not worsen acute intracerebral hemorrhage in mice

Tissue plasminogen activator (tPA) is the only FDA-approved treatment for reperfusing ischemic strokes. But widespread use of tPA is still limited by fears of inadvertently administering tPA in patients with intracerebral hemorrhage (ICH). Surprisingly, however, the assumption that tPA will worsen ICH has never been biologically tested. Here, we assessed the effects of tPA in two models of ICH. In a mouse model of collagenase-induced ICH, hemorrhage volumes and neurological deficits after 24 hrs were similar in saline controls and tPA-treated mice, whereas heparin-treated mice had 3-fold larger hematomas. In a model of laser-induced vessel rupture, tPA also did not worsen hemorrhage volumes, while heparin did. tPA is known to worsen neurovascular injury by amplifying matrix metalloproteinases during cerebral ischemia. In contrast, tPA did not upregulate matrix metalloproteinases in our mouse ICH models. In summary, our experimental data do not support the assumption that intravenous tPA has a deleterious effect in acute ICH. However, due to potential species differences and the inability of models to fully capture the dynamics of human ICH, caution is warranted when considering the implications of these findings for human therapy

MSJ741191_supplementary_appendix_a – Supplemental material for Fulminant rebound of relapsing–remitting multiple sclerosis after discontinuation of dimethyl fumarate: A case report

<p>Supplemental material, MSJ741191_supplementary_appendix_a for Fulminant rebound of relapsing–remitting multiple sclerosis after discontinuation of dimethyl fumarate: A case report by Peter Harmel, Frieder Schlunk and Lutz Harms in Multiple Sclerosis Journal</p

Treatment with FTY720 has no beneficial effects on short-term outcome in an experimental model of intracerebral hemorrhage

Background: No evidence-based therapy is available for patients with acute intracerebral hemorrhage (ICH). In view of the profound inflammatory reaction in the perilesional tissue, we investigated in a well-characterized experimental model whether the administration of the immunomodulator fingolimod (FTY720) is neuroprotective in acute ICH. Methods: ICH was induced by means of a stereotactic intrastriatal injection of collagenase type VII-S. FTY720 (1 mg/kg) was administered intraperitoneally 1 h after ICH induction. Hematoma volume was assessed spectrophotometrically at 24 h after ICH induction. The following endpoints were determined at 24 and 72 h, respectively: mortality rate and neurologic outcomes, edema formation, and MMP-9 activity. Results: Twenty-four hour after ICH induction, hematoma volume was not statistically different between groups. No difference was found in mortality and neurologic outcomes at 24 and 72 h between FTY720 treated mice and controls. Edema formation was present in both groups on the ipsilateral side with no statistical difference between groups at both time points. No difference was found in MMP-9 levels after 24 and 72 h between groups. Conclusions: Our results suggest that FTY720 has no beneficial effects in the acute phase of experimental ICH. Electronic supplementary material The online version of this article (doi:10.1186/s13231-016-0016-z) contains supplementary material, which is available to authorized users

Imaging-Based Outcome Prediction of Acute Intracerebral Hemorrhage

We hypothesized that imaging-only-based machine learning algorithms can analyze non-enhanced CT scans of patients with acute intracerebral hemorrhage (ICH). This retrospective multicenter cohort study analyzed 520 non-enhanced CT scans and clinical data of patients with acute spontaneous ICH. Clinical outcome at hospital discharge was dichotomized into good outcome and poor outcome using different modified Rankin Scale (mRS) cut-off values. Predictive performance of a random forest machine learning approach based on filter- and texture-derived high-end image features was evaluated for differentiation of functional outcome at mRS 2, 3, and 4. Prediction of survival (mRS ≤ 5) was compared to results of the ICH Score. All models were tuned, validated, and tested in a nested 5-fold cross-validation approach. Receiver-operating-characteristic area under the curve (ROC AUC) of the machine learning classifier using image features only was 0.80 (95% CI [0.77; 0.82]) for predicting mRS ≤ 2, 0.80 (95% CI [0.78; 0.81]) for mRS ≤ 3, and 0.79 (95% CI [0.77; 0.80]) for mRS ≤ 4. Trained on survival prediction (mRS ≤ 5), the classifier reached an AUC of 0.80 (95% CI [0.78; 0.82]) which was equivalent to results of the ICH Score. If combined, the integrated model showed a significantly higher AUC of 0.84 (95% CI [0.83; 0.86], P value &amp;lt;0.05). Accordingly, sensitivities were significantly higher at Youden Index maximum cut-offs (77% vs. 74% sensitivity at 76% specificity, P value &amp;lt;0.05). Machine learning-based evaluation of quantitative high-end image features provided the same discriminatory power in predicting functional outcome as multidimensional clinical scoring systems. The integration of conventional scores and image features had synergistic effects with a statistically significant increase in AUC

Non-contrast CT markers of intracerebral hemorrhage expansion: The influence of onset-to-CT time

Background: Hematoma expansion (HE) is an appealing therapeutic target in intracerebral hemorrhage (ICH) and non-contrast computed tomography (NCCT) features are promising predictors of HE. Aims: We investigated whether onset-to-CT time influences the diagnostic performance of NCCT markers for HE. Methods: Retrospective multicentre analysis of patients with primary ICH. The following NCCT markers were analyzed: hypodensities, heterogeneous density, blend sign, and irregular shape. HE was defined as growth &gt; 6 mL and/or &gt; 33%. We calculated the sensitivity, specificity, positive, and negative predictive values (PPVs and NPVs) of NCCT markers for HE, stratified by onset-to-CT time (&lt;2 h, 2-4 h, 4-6 h, &gt;6 h). Results: We included 1135 patients (median age 69, 53% males), of whom 307 (27%) experienced HE. Overall hypodensities had the highest sensitivity (0.68) and blend sign the highest specificity (0.87) for HE. Hypodensities were more common and had higher sensitivity (0.80) in patients with imaging within 2 h. The same result was observed for heterogeneous density, whereas irregular shape had a similar prevalence across time strata and higher sensitivity (0.79) beyond 6 h from onset. The frequency of blend sign increased with longer onset-to-CT time, whereas its specificity declined after 6 h from onset. Conclusion: The diagnostic performance of NCCT markers is influenced by imaging time. Hypodensities identified four out of five patients with HE within 2 h from onset, whereas irregular shape performed better in late presenters. Our findings may improve the use of NCCT markers in future studies and trials targeting HE