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Complex Clearance Mechanisms After Intraventricular Hemorrhage and rt-PA Treatment—a Review on Clinical Trials

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Abstract

Intracerebral hemorrhage in combination with intraventricular hemorrhage (IVH) is a severe type of stroke frequently leading to prolonged clinical care, continuous disability, shunt dependency, and high mortality. The molecular mechanisms induced by IVH are complex and not fully understood. Moreover, the treatment options for IVH are limited. Intraventricular recombinant tissue plasminogen activator (rt-PA) dissolves the blood clot in the ventricular system; however, whether the clinical outcome is thereby positively affected is still being debated. The mechanistic cascade induced by intraventricular rt-PA therapy may cure and harm in parallel. Despite the fact that intraventricular blood clots are thereby dissolved, blood derivatives enter the parenchyma and may still adversely affect functional structures of the brain: Smaller blood clots may obstruct the perivascular (Virchow-Robin) space and thereby the glymphatic system with detrimental consequences for cerebrospinal fluid (CSF)/interstitial fluid (ISF) flow. These clots, blood cells but also blood derivatives in the perivascular space, destabilize the blood-brain barrier from the brain parenchyma side, thereby also functionally weakening the neurovascular unit. This may lead to further accommodation of serum proteins in the ISF and particularly in the perivascular space further contributing to the adverse effects on the neuronal microenvironment. Finally, the arterial (Pacchionian) granulations have to cope with ISF containing this “blood, cell, and protein cocktail,” resulting in obstruction and insufficient function of the arterial granulations, followed by a malresorptive hydrocephalus. Particularly in light of currently improved knowledge on the physiologic and pathophysiologic clearance of cerebrospinal fluid and interstitial fluid, a critical discussion and reevaluation of our current therapeutic strategies to treat intraventricular hemorrhages are needed to successfully treat patients suffering from this severe type of stroke. In this review, we therefore summarize and discuss recent clinical trials and future directions for the field of IVH with respect to the currently increased understanding of the glymphatic system and the neurovascular unit pathophysiology.

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Acknowledgments

The authors acknowledge Sebastian Zachar, M.F.A. for creating the illustrations of Fig. 2 based on the drafts by BB and MM.

Funding

BB was supported by grants of the Deutsche Forschungsgemeinschaft (BO 4229/1-1, BO 4229/2-1, novel strategies to protect the neurovascular unit in cerebrovascular diseases) and PM by the European Union’s Seventh Framework Program (FP7/2008–2013) under grant agreement 627951 (Marie Curie IOF), the German Academic Exchange Service DAAD PPP Canada program with funds of the German Federal Ministry of Education and Research (BMBF, grant no. 57212163), and the German Federal Ministry of Education and Research (BMBF, grant no. 16GW0191). PM is a fellow of the BIH Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health.

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Authors and Affiliations

  1. Department of Neurocritical Care, Neurological and Neurosurgical First Stage Rehabilitation and Weaning, MediClin Klinik Reichshof, Berglandstr.1, 51580, Reichshof-Eckenhagen, Germany

    Bert Bosche

  2. Faculty of Medicine, Department of Neurology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany

    Bert Bosche

  3. Institute of Neurophysiology, Medical Faculty, University of Cologne, Cologne, Germany

    Bert Bosche, Jürgen Hescheler & Marek Molcanyi

  4. Department of Surgery, Division of Neurosurgery, Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada

    Bert Bosche

  5. Departments of Experimental Neurology and Neurology, Center for Stroke Research Berlin, NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Philipp Mergenthaler

  6. Berlin Institute of Health (BIH), Berlin, Germany

    Philipp Mergenthaler

  7. Department of Neurology, University of Göttingen Medical School, Göttingen, Germany

    Thorsten R. Doeppner

  8. Department of Neurosurgery, Research Unit for Experimental Neurotraumatology, Medical University Graz, Graz, Austria

    Marek Molcanyi

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Contributions

BB wrote the initial draft of the manuscript, which was intellectually extended by PM and MM, and finally re-edited by BB, PM, TD, JH, and MM. BB, TD, and MM created the drafts of the figures. All authors substantially contributed to the manuscript and approved the final version.

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Correspondence to Bert Bosche or Thorsten R. Doeppner.

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Bosche, B., Mergenthaler, P., Doeppner, T.R. et al. Complex Clearance Mechanisms After Intraventricular Hemorrhage and rt-PA Treatment—a Review on Clinical Trials. Transl. Stroke Res. 11, 337–344 (2020). https://doi.org/10.1007/s12975-019-00735-6

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