Navigating the ventricles: Novel insights into the pathogenesis of hydrocephalus

Abstract

Congenital hydrocephalus occurs in one in 500-1000 babies born in the United States and acquired hydrocephalus may occur as the consequence of stroke, intraventricular and subarachnoid hemorrhage, traumatic brain injuries, brain tumors, craniectomy or may be idiopathic, as in the case of normal pressure hydrocephalus. Irrespective of its prevalence and significant impact on quality of life, neurosurgeons still rely on invasive cerebrospinal fluid shunt systems for the treatment of hydrocephalus that are exceptionally prone to failure and/or infection. Further understanding of this process at a molecular level, therefore, may have profound implications for improving treatment and quality of life for millions of individuals worldwide. The purpose of this article is to review the current research landscape on hydrocephalus with a focus on recent advances in our understanding of cerebrospinal fluid pathways from an evolutionary, genetics and molecular perspective.

Keywords: Choroid plexus; Ependymal cells; Glymphatic system; Hydrocephalus.

Figure 1

Evolutionary relationships of CSF and the glymphatic system. A. In mammals, the internal CSF (ICSF) is secreted by the choroid plexus (CP) and is continuous with the external CSF (ECSF) or subarachnoid space via the foramina of the fourth ventricle. B. In cyclostomes, elasmobranchs, teleosts and dipnoans, the ICSF is not in communication with an ECSF compartment but may be able to pass into the pericerebral connective tissue (CT). C. In amphibians, reptiles and birds, there is an absence of a metapore or foramen, however, ICSF is thought to pass through a permeable membrane to reach the ECSF compartment. Note that absorption through arachnoid villi (AV) only occurs in certain mammalian species, as shown in A. Modified from. D. CSF circulation in humans, and a closer image of the glymphatic system (E) showing the flow of fluid within the interstitial compartment from periarterial to perivenous spaces in the brain. Astrocytic endfeet make up a significant part of the blood brain barrier and aquaporin-4 has been shown to regulate extracellular fluid volume.

Figure 2

Choroid plexus epithelial cells and ventricular ependymal cells. A. General sketch of CSF flow within the human brain with magnification of the choroid plexus and ventricular ependymal cells in B. The choroid plexus is composed of modified ependymal cells with tight junctions and a stromal layer with fenestrated capillaries. This layer is continuous the ependymal cells lining the ventricle, which are connected via gap junctions. The apical membrane of choroid plexus epithelium faces the internal CSF compartment. C. Important channels in the apical and basolateral membranes of choroid plexus epithelial cells. NKCC1 is predominantly located on the apical membrane, where it plays an important role in the production of CSF through the activation of aquaporin-1 channels, which have been found both on apical and basolateral membranes but predominantly on the apical side of CPECs.