December 2, 2005
Miles Johnston, Ph.D., Department of Laboratory Medicine and Pathobiology, Neuroscience Research, Sunnybrook and Women's College HSC, University of Toronto

Defining the linkage between cerebrospinal fluid and extracranial lymphatics: creating the framework for a new understanding of CSF disorders

Cerebrospinal fluid (CSF) bathes the brain and spinal cord and is located within the ventricular system and subarachnoid space. Under normal circumstances, this fluid contributes to the biophysical properties of the brain, helps to prevent the brain from injury and provides a medium through which molecular signals are conveyed. Unfortunately, diseases associated with the CSF system are not uncommon. For example, hydrocephalus continues to pose significant challenges to the biomedical community. Although many modifications in shunt design have been made over the last 50 years, patient outcomes with CSF diversion have not improved significantly. In addition, the causes of many of these diseases remain unknown. Therefore, it seems appropriate to question the central tenets on which our understanding of CSF dynamics is based. In particular, it seems highly unlikely that obstruction of the arachnoid villi and granulations (the generally accepted sites for CSF transport) is the major causal factor in these conditions. If we believe that impaired CSF clearance has some contributing role in the pathogenesis of these diseases, it seems appropriate to consider alternative concepts. In this regard, the textbook view of CSF absorption is being challenged by studies that support a major role for the lymphatic circulation in CSF transport. There are many potential sites at which lymphatics may gain access to CSF but the primary pathway involves the movement of CSF through the cribriform plate foramina in association with the olfactory nerves. Lymphatic vessels fuse with the sheaths of the olfactory nerves and form a collar around the nerve fibers on the extracranial surface of the cribriform plate. Qualitative approaches reveal that lymphatic CSF transport occurs in essentially all mammals including human and non-human primates. Additionally, the ability of extracranial lymphatic vessels to absorb CSF develops around the time that significant volumes of CSF are being produced by the choroid plexus. The major focus of this presentation is to discuss the various methods we have used to quantify lymphatic CSF transport including subarachnoid infusion studies, the use of radioactive tracers in combination with mass balance equations and surgical techniques that permit the obstruction of the most relevant pathways. The various experimental approaches lead to the same conclusion; lymphatic vessels have the primary role in CSF absorption. Current efforts are directed at developing experimental approaches to investigate the pathogenesis of CSF disorders that reflect our new understanding of CSF absorption mechanisms and pathways.