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

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.