Emerging Concepts of Cerebrospinal Fluid Physiology and Communicating Hydrocephalus

CHAPTER 49 Emerging Concepts of Cerebrospinal Fluid Physiology and Communicating Hydrocephalus

New data are modifying our classic concepts of cerebrospinal fluid (CSF) production, flow, and reabsorption.1,2 Consequently, they are calling into question our present understanding of the cause and nature of hydrocephalus.35 Classically, hydrocephalus has been considered to result from an imbalance in the formation, flow, or absorption of CSF with abnormally increased CSF volume and/or pressure. Increasingly, hydrocephalus is now believed to result from disordered pressure/volume relationships (compliance) within the intracranial-intraspinal compartments.35 The information presented here builds on that in Chapter 48 to present some emerging concepts of CSF physiology and hydrocephalus. In some cases, the data appear conflicting. Nonetheless, it is hoped that a broader understanding of normal and deranged CSF physiology may lead to improved diagnosis and treatment of hydrocephalus in the future.

The following definitions are provided for a better understanding of the concepts discussed:


CSF Volume

Classically, the total volumes of CSF have been given as 40 to 60 mL in infants, 60 to 100 mL in children, and about 150 mL in adults.68 The volume of the adult ventricles has been considered to be 25 to 30 mL. Recent work now suggests that the total CSF volume is much higher: perhaps 150 mL in the intracranial subarachnoid space, 100 to 120 mL in the spinal subarachnoid space, plus 100 to 300 mL of interstitial fluid within the central nervous system.912

Interstitial Fluid Production

Interstitial fluid is most likely produced by active transport across the capillary endothelium and as a by-product of the metabolic activity of the brain (Figs. 49-2 and 49-3).1214 A portion of the interstitial fluid may also be recycled CSF that reenters the brain via the arterial perivascular spaces along the ventral surface of the brain.12

CSF Production

Classically, 60% to 90% of CSF was thought to be produced within the ventricular system by the choroid plexus and 10% to 40% within the brain by active transport across the capillary endothelium into the brain.7,8 Recent work now suggests that fluid is produced everywhere in the central nervous system (see Figs. 49-2 and 49-3).1,2 Much of that fluid forms first as interstitial fluid, which then rapidly exchanges and mixes with the CSF across the pia, ependyma, and perivascular spaces.1,2,12 Chemically, the interstitial fluid and CSF have very similar compositions and are nearly indistinguishable from each other.13 The volume of CSF produced by the spinal cord is considered to be negligible.

Quantitatively, CSF production has been estimated at 0.305 ± 0.145 mL/min or about 600 mL/day.15 This volume markedly exceeds the ventricular CSF volume of 25 to 30 mL but is small when compared with the cerebral blood flow of 750 mL/min. The turnover time for CSF is 5 to 7 hours, so the total CSF volume is renewed about 4 times a day.11 The rate of fluid secretion by the choroid plexus depends, in part, on the perfusion pressure of the blood. With rising intracranial pressure, CSF production decreases.2

CSF Reabsorption

Classically, most CSF was believed to be reabsorbed within the head through the arachnoid granulations situated along the dural venous sinuses (85% to 90%). The rest was believed to be absorbed within the spine along the root sheaths of the spinal nerves (10% to 15%).16,17


The arachnoid villi/granulations have been thought to act as mechanical valves to regulate passage of CSF into the dural venous sinuses.18 Di Chiro demonstrated that radioisotope injected into the lumbar CSF passed superiorly within the CSF and accumulated over the cerebral convexities in relation to the arachnoid granulations.19 This was taken to be support for the role of the arachnoid granulations in CSF reabsorption.19 To date, however, no experimental evidence actually proves that fluid is transported across the arachnoid villi in normal individuals. Indeed, in children, arachnoid granulations do not develop until after the fontanelles close, so, in children, CSF reabsorption must be accomplished by a different mechanism.20


It is known that radiolabeled albumin injected into the lumbar subarachnoid space becomes detectable in the blood stream just minutes after injection, well before it could ascend through the spinal canal into the head.bib14311 Bozanovic-Sosic and colleagues tried to estimate the percent clearance of CSF from the intracranial versus the intraspinal compartments by placing an extradural ligature around the thecal sac between C1 and C2 and instilling into the CSF human serum albumin radiolabeled with two different isotopes, one isotope for each compartment. They found that the spinal compartment accounted for approximately 25% of the total clearance of the albumin.16

Alternate Pathways

Alternate pathways for CSF reabsorption have been documented in animals and humans.2027 Physiologic evidence suggests that these alternate pathways are a significant route, perhaps the dominant route, for CSF reabsorption at normal CSF pressures.28 With elevated pressure, absorption may take place via the arachnoid granulations. At elevated pressures, CSF may also pass into the dura through “clefts” that convey the CSF to the venous sinuses.16,29,30

Lymphatic Drainage

There are no conventional lymphatic channels within the brain. Nonetheless, there is a substantial flow of interstitial fluid and CSF from the brain to the cervical lymph nodes. In animals such as rodents and sheep, up to 50% of CSF drains from the subarachnoid space to the cervical and lumbar lymph nodes along cranial and spinal nerve roots (Fig. 49-4).24 The percent in humans is not yet established.

Weller has shown that the interstitial fluid and the CSF drain to the cervical lymph nodes by two different paths.23,24

Drainage of Interstitial Fluid (Path 1)

Interstitial fluid and solutes appear to drain from the brain along the 100 to 150 nm wide basement membranes in the capillary walls and then continue onward along the basement membranes between the smooth muscle cells in the tunica media of the arteries (Fig. 49-5).23,24 The interstitial fluid and solutes then enter the adventitia around the leptomeningeal arteries and continue through the base of the skull along the carotid artery (and probably the vertebral artery) to the cervical lymph nodes.23 A layer of pia-arachnoid separates the adventitia of the leptomeningeal arteries from the CSF in the subarachnoid space.23

The motive force for this “lymphatic” flow appears to be the pulse wave traveling along the arteries.23 Perivascular lymphatic drainage is seen only in living animals and ceases immediately after cardiac arrest.24 It likely proceeds as follows: with each pulsation, an arterial pressure wave passes antegrade along the vessel. After each pulse wave there is a contrary (or reflection) wave traveling in the reverse direction—retrograde. This contrary wave may drive the perivascular lymphatic drainage out of the brain. A valve-like action to prevent backflow may be provided by the change in the configuration of the basement membrane from its sheet-like, stretched, distended position in systole to its folded recoil position in diastole.23 Normal innervation of the vessels is also needed for perivascular “lymphatic” flow. In rabbits, cholinergic deafferentation of these vessels appears to reduce perivascular drainage.23

Parenchymal Veins

CSF reabsorption may also take place through the parenchymal veins. It is now accepted that there is full physiologic continuity and exchange between the interstitial fluid and the CSF at the walls of the brain capillaries (see Fig. 49-2).1214 The surface area of the cerebral capillaries has been estimated at 240 cm2 per gram of tissue.31 For a human brain of 900 to 1500 grams (wet weight, unfixed), this predicts a very large surface area of vessels to absorb interstitial fluid (perhaps 200,000 to 350,000 cm2).31 The surface area of the arachnoid villi and perineural sheaths is not more than 10 cm2.2 The parenchymal capillaries are known to actively absorb the macromolecules and plasma proteins present in the CSF and regulate fluid homeostasis at a slightly positive intracranial pressure. Therefore, it is likely that CSF may also be reabsorbed across the walls of the parenchymal veins (see Fig. 49-3). Interestingly, aquaporin-4 is upregulated in hydrocephalus, further suggesting the CSF is absorbed into the blood from the edematous periventricular white matter.23

Physical Activity

The rate of absorption of macromolecules within the CSF also depends, in part, on the physical activity of the person or experimental animal. Mixing of tritiated inulin within the CSF and its bidirectional distribution throughout the CSF volume is greatly increased by respiratory and body movements.31 Similarly, in patients injected with the radionuclide tracer technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA), the rate of absorption of the tracer is higher in active than resting individuals. In one experimental study of radionuclide tracer injected into the lumbar spinal canal, the activity decreased 20% (±13%) in the first hour, higher in active than resting individuals, with no correlation between radionuclide reduction, intraspinal movement of the tracer, or the rate of CSF production.17

Low Pressure Versus High Pressure

The sites and proportions of CSF absorption may vary with the intracranial pressure. For example, when radioiodinated serum albumin (RISA) is infused into the CSF of cats and rabbits under normal pressure, it stays mainly in place. When the RISA solution is infused under increased CSF pressure, however, the RISA shows a greatly increased concentration in the optic nerves, olfactory bulbs, episcleral tissue, and deep cervical lymph nodes.31 When a solution of horseradish peroxidase (HRP) is infused into the CSF under normal CSF pressure, it remains within the CSF. When the solution is infused under high pressure, the high pressure damages the layers of arachnoid connected by tight junctions adjacent to the dura and the HRP then enters the highly vascularized dura. Furthermore, when HRP is infused under high pressure (1) the endothelial cells of the arachnoid villi develop vesicles and transcellular channels and (2) the resistance to fluid infusion decreases greatly, indicating nonphysiologic increase in fluid absorption.31 Nagra and associates concluded that “the available data suggest that CSF transport can occur into the cranial venous system but only at high intracranial pressures.”3234

Compliance and Pressure/Volume Relationships

Compliance (C) is the ratio of a volume change (ΔV) to the pressure change (ΔP) that is induced by that incremental change in volume. Compliance is given as C = ΔV/ΔP.1 In a highly compliant system, a large increase in volume will cause only a small change in pressure. That is, the compliant brain can accommodate a substantial increase in ventricular volume with little increase in intracranial pressure. In a less compliant system, the brain is more rigid, so even small increases in volume cause large increases in intracranial pressure.

This pressure/volume relationship is exponential (Fig. 49-9).1 The change in pressure caused by any increment in volume increases exponentially as the mean pressure rises. Put differently, as the mean pressure rises, the system becomes more rigid and more sensitive to slight variations in volume.1 For the brain, the overall compliance is composed of the actual compliance of the brain tissue (small), the arterial compliance, the venous compliance, and the compliance of the spinal thecal sac.

Hydrodynamics of CSF

It remains uncertain whether the passage of CSF through the ventricular system results from (1) bulk flow driven down a pressure gradient from the ventricle to the subarachnoid space, (2) flow swept onward by the coordinated beating of the ciliated ependyma of the ventricular walls, and/or (3) rhythmic flow generated by the cycles of cardiac pulsation.35,36

Bulk Flow of CSF

Dandy35 showed that plugging the aqueduct in dogs caused dilation of the ventricles proximal to the obstruction and took this as evidence for bulk directional flow of CSF. Bulat and colleagues question the very concept of bulk flow of CSF through the ventricular system.13,14

Jan 22, 2016 | Posted by in NEUROLOGICAL IMAGING | Comments Off on Emerging Concepts of Cerebrospinal Fluid Physiology and Communicating Hydrocephalus

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