Cerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases

Abstract

The fine balance between the secretion, composition, volume and turnover of cerebrospinal fluid (CSF) is strictly regulated. However, during certain neurological diseases, this balance can be disrupted. A significant disruption to the normal CSF circulation can be life threatening, leading to increased intracranial pressure (ICP), and is implicated in hydrocephalus, idiopathic intracranial hypertension, brain trauma, brain tumours and stroke. Yet, the exact cellular, molecular and physiological mechanisms that contribute to altered hydrodynamic pathways in these diseases are poorly defined or hotly debated. The traditional views and concepts of CSF secretion, flow and drainage have been challenged, also due to recent findings suggesting more complex mechanisms of brain fluid dynamics than previously proposed. This review evaluates and summarises current hypotheses of CSF dynamics and presents evidence for the role of impaired CSF dynamics in elevated ICP, alongside discussion of the proteins that are potentially involved in altered CSF physiology during neurological disease. Undoubtedly CSF secretion, absorption and drainage are important aspects of brain fluid homeostasis in maintaining a stable ICP. Traditionally, pharmacological interventions or CSF drainage have been used to reduce ICP elevation due to over production of CSF. However, these drugs are used only as a temporary solution due to their undesirable side effects. Emerging evidence suggests that pharmacological targeting of aquaporins, transient receptor potential vanilloid type 4 (TRPV4), and the Na⁺-K⁺-2Cl^- cotransporter (NKCC1) merit further investigation as potential targets in neurological diseases involving impaired brain fluid dynamics and elevated ICP.

Keywords: Blood–brain barrier; Cerebrospinal fluid dynamics; Choroid plexus; Intracranial pressure elevation; Ischaemic stroke.

Fig. 1

Conventional view of CSF flow. CSF is produced in the ventricles, beginning in the lateral ventricles, and flows toward the subarachnoid space. CSF circulates in the subarachnoid space and drains into the subarachnoid space (via arachnoid projections) and the spinal cord. Arrows depict the flow of CSF from the lateral ventricle origin

Fig. 2

Transepithelial ion transport at the choroid plexus. Movement of solutes from the interstitial space to the intracellular environment via the basolateral membrane are shown—AE2 (epithelial anion exchanger 2), AQP1 (aquaporin 1), NBC (sodium bicarbonate coexchanger) and KCC2 (potassium chloride cotransporter). The movement from the intracellular environment to the CSF in the ventricles via the apical membrane is also shown—Na⁺–K⁺–ATPase, AQP1, NKCC1 (sodium–potassium-chloride cotransporter 1), NHE (sodium–hydrogen exchanger) and K⁺ channel

Fig. 3

Representation of the relationship between the Monro–Kellie hypothesis, intracranial pressure (ICP) and cerebral perfusion pressure (CPP). Values are based on a baseline mean arterial pressure (MAP) of 80 mmHg. In the compensated model, an increase in cerebral blood volume produces a decrease in cerebrospinal fluid (CSF) volume; this allows ICP and CPP to remain at baseline level. In the model of no compensation, there is no decrease in either cerebral blood volume or brain tissue following an increase in CSF volume; this causes ICP to rise to pathological levels and CPP to decrease in line with the relationship between CPP and ICP (CPP = MAP − ICP)