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Cerebrospinal fluid physiology and dynamics
Introduction
The discovery, physiology, and flow of the mysterious “liquor cerebrospinalis” has been an ongoing debate and topic of inquiry which continues in the present time. The great Greek physician Hippocrates (460–370 bc ) embraced the ancient theory of “humoralism” and developed it into a medical theory. It ascribed certain illnesses, emotions, and behavior to an excess or lack of body fluids. This line of thinking was extended for centuries by Greek, Persian, Roman, and Islamic physicians until the mid-16th century.
Galen (130–200 ad ), the premier anatomist before Vesalius (1514–1564), referred to “excremental liquid” in the ventricles of the brain from where it is purged into the nose. Remarkably, this theory was accepted for more than 1000 years. In 1761, Cotugno gave the first reliable account of ventricular and subarachnoid fluid. However, it still took a long time for full acceptance of the cerebrospinal fluid (CSF) as a physiological fluid filling the ventricles and the subarachnoid spaces. Miller described the first nontraumatic nasal CSF leak in 1826 in a child with hydrocephalus. Key and Retzius performed anatomic studies published in 1875 of a description of the routes of CSF flow. This work led to Harvey Cushing’s interest in CSF and his characterization of the circulation of CSF as the “third circulation.” His article, “The Third Circulation and its Channels,” published in 1925, established CSF physiology as an important aspect of neuroscience.
In recent decades, there has been a proliferation of scientific publications, dedicated journals, and even specialized associations related to the study of CSF. In addition, the role of CSF is increasingly examined beyond neuroscience in the fields of oncology, endocrinology, geriatric medicine, and psychiatry.
Regarding CSF rhinorrhea, the past century has seen progressive innovation in techniques for surgical repair. Dandy reported successful intracranial repair in 1929 followed by various extracranial approaches, culminating in the currently favored intranasal endoscopic technique described by Wigand in 1981. In addition, there is an increasing awareness of the role of CSF physiology and dynamics in making the correct diagnosis and treating CSF leaks successfully.
Physiology
Secretion
Cerebrospinal fluid is formed by a combination of passive capillary blood filtration and active epithelial secretion in the central nervous system (CNS). This traditional understanding has been that about 80% of CSF production occurs via a network of modified ependymal cells called the choroid plexus and the remaining 20% from brain parenchyma. Furthermore, the belief has been that most absorption occurs at the arachnoid villi (90%) and a smaller amount directly into cerebral venules (10%). Challenging these concepts are novel modern insights using molecular and cellular biology as well as neuroimaging, which indicate that CSF physiology may be much more complex than previously believed.
The CSF circulation consists of not only a directed flow of CSF but also a pulsatile to-and-fro movement throughout the entire brain. Local fluid exchange occurs continuously between blood, interstitial fluid (ISF), and CSF. It is also believed that CSF moves through the ventricles and the brain cisterns, circulates in the subarachnoid spaces, and is ultimately absorbed into the venous blood at the level of the arachnoid villi. Minor portions of CSF, perhaps more than previously thought, may be drained into the cervical lymphatics that run via the perineural spaces of the cranial nerves (CNs).
Cerebrospinal fluid is excreted by the choroid plexus in the lateral, third and fourth ventricles of the brain. The epithelial cells of the choroid plexus secrete CSF by a process that involves the movement of Na + , Cl - , and HCO3 - from the blood to the ventricles of the brain. This creates an osmotic gradient, which drives the secretion of H 2 O. The unidirectional movement of the ions is achieved because of the polarity of the epithelium, that is, the ion transport proteins in the blood-facing (basolateral) are different from those in the ventricular (apical) membranes. The capillary–astrocyte complex of the blood–brain barrier has also been implicated as an active producer of brain ISF ( Fig. 5.1 ). Although the ISF is continuous with the CSF, the composition of the former can dramatically differ in ions where neuronal activity occurs.
The rate of ISF formation was estimated from the clearance rate of tracer substances, which were injected into the brain parenchyma. It was assumed that the rate of clearance provides an estimate of the rate of ISF secretion at the blood–brain barrier. The ISF secreted at the blood–brain barrier is coupled with shifts of extracellular fluid between brain and CSF, eventually leading to the net formation of CSF.
Aquaporins (AQPs) are channel proteins that form pores in cell membranes that facilitate transport of water. Cerebral AQPs, mainly AQP1 and AQP4, have been proposed to play a relevant function on CSF and ISF homeostasis. Based on their expression pattern, AQP1 are expressed only in the choroid plexus epithelial cells, and AQP4 in ependymal cells and glia limitans, including pericapillary astrocyte foot processes. This provides a simplistic view of their function and associates AQP1 to CSF production and AQP4 to CSF and ISF exchange and absorption.
The final composition of the CSF is similar to blood plasma but contains lower concentration of potassium, bicarbonate, calcium, and glucose and higher concentrations of sodium, magnesium, and chloride. The protein and cholesterol contents are very low. Higher pCO 2 (50 mm Hg) results in a lower pH (7.33) than that of blood (7.35–45).
The role of pressure gradients in CSF secretion is unclear. If pressure gradients were the primary driver of CSF secretion, then this would suggest that it is a fluid derivative of serum, produced from ultrafiltrate. This is contrasted in various studies of CSF regulation in which its ability to independently regulate its ionic milieu has been demonstrated because the composition of ions in CSF differs significantly from that of plasma. , The protein content of CSF (0.03 g/dL) is lower than that of plasma (7 g/dL), with a CSF-to-plasma ratio of 0.004. Additionally, alterations in CSF osmolarity have been shown to influence water flux across the choroid plexus and the blood–brain barrier. This series of experiments was performed by Klarica et al. with the aim of disproving this traditional view of CSF secretion. However, the influence that altered osmolarity exerts on water flux is not contradictory to the currently accepted hypothesis and in fact suggests mechanisms of CSF homeostasis that are dependent on osmolarity ( Table 5.1 ).
TABLE 5.1
Composition of Plasma and Cerebrospinal Fluid
| Plasma | CSF | |
| Na+ (mM/L) | 153 | 147 |
| K+ (mM/L) | 4.7 | 2.9 |
| Ca2+ (mM/L) | 1.3 | 1.1 |
| Mg2+ (mM/L) | 0.6 | 1.1 |
| Cl− (mM/L) | 110 | 113 |
| HCO 3 − (mM) | 24 | 22 |
| pH | 7.40 | 7.33 |
| Osmolarity (mOsm) | 290 | 290 |
The involvement of carbonic anhydrase in the CSF secretion process has been targeted therapeutically in the treatment of patients with hydrocephalus and idiopathic intracranial hypertension (IIH) with the use of acetazolamide. This medication acts as an inhibitor of the sulfonamide-sensitive carbonic anhydrases and reduces CSF secretion by approximately 50%. This highlights the importance of HCO 3 − within the choroid plexus epithelium and provides further evidence of the tissue’s role as an important site of CSF secretion. In addition, recent reviews of acetazolamide as a preoperative strategy for reducing CSF rhinorrhea and associated elevated intracerebral pressure (ICP) are promising, further supporting carbonic anhydrase as a target for attenuating ICP.
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