Lymphatic outflow of cerebrospinal fluid is reduced in glioma

Qiaoli Ma,Markus Rudin,Michael Weller,Yann Decker,Steven T Proulx,Hannah Schneider,Felix Schlegel,Michael Detmar,Samia B Bachmann

doi:10.1038/s41598-019-51373-9

Abstract

Glioblastoma is a malignant brain tumor with mean overall survival of less than 15 months. Blood vessel leakage and peritumoral edema lead to increased intracranial pressure and augment neurological deficits which profoundly decrease the quality of life of glioblastoma patients. It is unknown how the dynamics of cerebrospinal fluid (CSF) turnover are affected during this process. By monitoring the transport of CSF tracers to the systemic blood circulation after infusion into the cisterna magna, we demonstrate that the outflow of CSF is dramatically reduced in glioma-bearing mice. Using a combination of magnetic resonance imaging (MRI) and near-infrared (NIR) imaging, we found that the circulation of CSF tracers was hindered after cisterna magna injection with reduced signals along the exiting cranial nerves and downstream lymph nodes, which represent the major CSF outflow route in mice. Due to blockage of the normal routes of CSF bulk flow within and from the cranial cavity, CSF tracers were redirected into the spinal space. In some mice, impaired CSF clearance from the cranium was compensated by a lymphatic outflow from the sacral spine.

Highlights

Glioblastoma arises from astrocytes and is classified as World Health Organization Grade 4 infiltrative glioma
One might expect that Cerebrospinal fluid (CSF) outflow would increase during glioblastoma development, as high intracranial pressure might appear to be a powerful drive for fluid to exit the skull
We previously demonstrated that outflow of CSF occurs predominantly through lymphatic vessels, and by dynamic imaging of the posterior facial vein that collects blood from the transverse sinus in mice, we excluded a direct route from CSF to blood[9]

Summary

Introduction

Glioblastoma arises from astrocytes and is classified as World Health Organization Grade 4 infiltrative glioma. As expected from a bulk outflow system, the dynamics of CSF outflow are accelerated under conditions of acute rises in intracranial pressure such as the introduction of large CSF infusion volumes[10,11,12] It is not yet clear how CSF outflow is altered during pathological conditions, such as the vasogenic edema that occurs in glioblastoma. Edema may alternatively lead to a slower turnover of CSF due to reductions in CSF formation and/or blocked outflow routes It is highly interesting and clinically relevant to study the changes in CSF outflow that occur in glioblastoma. This might potentially lead to novel interventions for brain www.nature.com/scientificreports/. Mice showing high tracer signal in the sacral region of the spine demonstrated lymphatic outflow to iliac lymph nodes and more tracer transport to systemic blood, indicating that CSF may be redirected in glioma-bearing mice to spinal lymphatic outflow pathways after the blockage of cranial CSF outflow routes

Methods

Results

Conclusion