Production and Flow of Cerebrospinal Fluid

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CHAPTER 33 Production and Flow of Cerebrospinal Fluid

Continually generated and flowing cerebrospinal fluid (CSF) is vital for brain homeostasis.¹ Day and night, the choroid plexus churns out fluid into the ventricles. CSF formation is about 0.4 mL/min per gram of choroid plexus. Nascent CSF is more than a passive ultrafiltrate of plasma.² Active secretion by choroidal epithelium is exquisitely modulated so that intracranial pressure (ICP) is stable if CSF absorption is normal. A tenth of the choroidal blood flow of about 4 mL/min per gram³^,⁴ becomes new CSF in the ventricular spaces.

Multisource evidence indicates that 70% to 80% of CSF is formed by the plexuses in the lateral, third, and fourth ventricles. Human CSF elaboration is mechanistically similar to that in many mammalian species. Extrachoroidal formation of a CSF-like fluid occurs at the cerebral capillary wall,⁵ but it is less efficient compared with choroid plexus generation. A lavish turnover of fluid at the blood-CSF interface (choroidal epithelium) is engendered by a high blood flow to the plexus, substantial activities of Na⁺,K⁺-ATPase⁶^,⁷ and carbonic anhydrase,⁸^,⁹ and a plethora of ion transporters. Stable composition is the hallmark of CSF. Extracellular ion stability is essential to neurotransmission.

Intricate Fluid Balance Within the Central Nervous System

To preserve sound ICP and volume, the central nervous system (CNS) relies on a battery of choroidal and extrachoroidal fluid-regulating mechanisms.² Orderly CSF percolation depends on simultaneous, precisely controlled solute and water fluxes at several transport interfaces among blood, CSF, and brain.¹⁰ The choroid plexus at the blood-CSF border is at the heart of fluid dynamics in the CNS. This industrious secretory epithelium provides a steady fluid output that has an impact on the biochemical and biophysical integrity of the brain. Disturbance of CSF flow disrupts extensive exchange between large-cavity CSF and brain interstitial fluid.¹¹ Accordingly, the diminution of CSF formation and turnover rate in disease¹² and senescence sets into motion many pathophysiologic cascades.

Variation in Cerebrospinal Fluid Production

Because CSF dynamics have an impact on brain metabolism, it is important to assess optimal CSF formation rate in health. Adult humans normally form CSF at about 0.35 mL/min.¹^,² Nocturnally elevated CSF production¹³ may relate to altered cerebral metabolism during sleep. CSF formation also fluctuates in disease.¹⁴ Neurosurgeons face pathophysiologic situations in which the choroid plexus forms too much or not enough fluid. With hypersecreting choroid plexus papillomas,¹⁵^,¹⁶ surgical excision often reduces ICP. With hyposecreting choroid plexus, as in normal-pressure hydrocephalus (NPH) and Alzheimer’s disease (AD), the stagnated CSF turnover rate¹⁷^,¹⁸ may contribute to cerebral dysfunction. Disease-modified fluid formation by the choroid plexus can thus harm CSF dynamics and the extracellular environment of neurons.¹¹ Accordingly, imbalanced CSF formation necessitates surgical or pharmacologic remediation.

Mechanisms of Cerebrospinal Fluid Formation by Choroid Plexus

Penetration of ions and water into the CNS occurs predominantly across the choroid plexus.² Control of brain fluid balance therefore starts with a thorough knowledge of choroidal transport mechanisms. Fluid secretion into the ventricles is mediated by an array of ion transporters asymmetrically positioned at the blood- and CSF-facing membranes.² Structurally and functionally, the choroid plexus epithelium resembles the kidney proximal tubule.¹⁹ Renal-like organs are designed to transfer a copious volume of fluid.

CSF production is directly proportional to the net transfer of Na⁺ and Cl⁻ from blood to ventricles.²⁰^–²² Conversely, when CNS-inward Na⁺ and Cl⁻ transport across the choroid plexus is reduced, CSF formation is attenuated.²³^,²⁴ The driving force for ion movements across choroid plexus membranes is a downhill (energetically speaking) concentration or electrochemical gradient. For the external limiting membranes of the choroid plexus, the direction of the gradients for Na⁺, Cl⁻, K⁺, and HCO₃⁻ is given in Figure 33-1. Na⁺ entry into choroid plexus epithelium is downhill (gradient-wise) from plasma across the basolateral membrane. At the other side of the choroid cell, K⁺, Cl⁻, and HCO₃⁻ move downhill across the apical membrane into CSF. However, both basolaterally and apically, these downhill ionic movements are facilitated by uphill active transport (requiring chemical energy as ATP) by the primary Na⁺ pump (Fig. 33-2). Active Na⁺ pumping into CSF keeps choroid cell Na⁺ concentration relatively low,⁷ thereby establishing a basolateral inward driving force for Na⁺ from plasma into epithelium.²⁵

FIGURE 33-1 Ionic gradients across choroid plexus membranes that drive secretion of CSF. The continual streaming across the choroid plexus of the CSF, a fluid rich in Na⁺, K⁺, Cl⁻, and HCO₃⁻ (A), is the result of regulated transport and permeability to various ions and water. As the result of active extrusion of Na⁺ by the choroid plexus into CSF, a downhill gradient for Na⁺ is set up across the opposite basolateral membrane (B). This inward Na⁺ gradient promotes transfer of plasma-derived Na⁺ into the choroid plexus epithelium through ion cotransport or exchange. Cl⁻, HCO₃⁻, and K⁺ ions that are loaded into the choroid plexus are subsequently released through channels or cotransporters down their respective electrochemical gradients into ventricular CSF.

(From Johanson CE, Duncan JA 3rd, Klinge PM, et al. Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res 2008;5:10.)

FIGURE 33-2 Choroid plexus basolateral and apical membrane transport mechanisms that are involved in CSF formation and homeostasis. Interstitial Na⁺, Cl⁻, and HCO₃⁻ are actively accumulated by choroid plexus epithelium by transporters in the basolateral membrane. Additional HCO₃⁻ is generated intracellularly by carbonic anhydrase. K⁺, Cl⁻, and water diffuse through channels down their gradients from cytoplasm into CSF. Na⁺ and HCO₃⁻ move into the ventricles by apical membrane cotransporters. Na⁺ is also actively extruded into CSF by the Na⁺ pump, which cycles K⁺ across the apical membrane. K⁺-Cl⁻ cotransport helps stabilize cell volume as CSF is formed. CSF production is essentially the net transport of Na⁺, K⁺, Cl⁻, HCO₃⁻, and water from blood to ventricles.

(From Johanson CE, Duncan JA 3rd, Klinge PM, et al. Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res 2008;5:10.)

Epithelial transport polarity is fundamental to fluid formation. Polar distribution (sidedness) of specific active transporters and passive channels enables net fluid movement from blood to CSF (see Fig. 33-2). Basolateral (vascular) and apical (CSF) transporters and channels thus mediate the streaming of ions and water. Directionally, the fluxes are mainly from interstitium to parenchyma to ventricles. Figure 33-2 schematizes the polar distribution of primary and secondary active ion transporters. Channels allow passive diffusion of K⁺ and Cl⁻ (apical efflux) into nascent CSF.²⁶ Many ionic species are involved in CSF production (e.g., K⁺, Mg²⁺, and Ca²⁺). However, fluid formation is primarily (quantitatively) generated by net secretion of Na⁺, Cl⁻, and HCO₃⁻. Water osmotically follows ion transport across the apical membrane (see Fig. 33-2). Such transfers occur by stepwise and parallel processes described in the following sections.

Sodium

Energetically, the pivotal initiating step in CSF formation is the primary active transport of Na⁺ from choroidal epithelium to ventricle.²⁷ Na⁺,K⁺-ATPase activity empowers this Na⁺ pumping by generating ATP (see Fig. 33-2). To stabilize choroid pH and epithelial volume²⁵^,²⁸ while CSF is elaborated, the Na⁺ efflux (apically) is balanced by continual Na⁺ influx (basolaterally) through Na⁺-H⁺ exchange and Na⁺ inward transport coupled with HCO₃⁻.²⁹^,³⁰

Chloride

As the main anion in CSF secretion, Cl⁻ is actively transported across the basolateral membrane in exchange for cellular HCO₃⁻_.³¹ This pulls plasma Cl⁻ into the epithelium for accumulation above electrochemical equilibrium.³² Under some conditions, intraepithelial Cl⁻ diffuses into CSF through the efflux arm of the Na⁺-K⁺-Cl⁻ cotransporter.³³ However, the downhill diffusion of Cl⁻ into CSF by way of apical Cl⁻ channels is likely to be the main pathway by which Cl⁻ accesses the ventricles to sustain fluid formation.²⁶

Bicarbonate

HCO₃⁻ in choroid plexus has a dual source. First, carbonic anhydrase catalyzes the hydration of CO₂ to form H⁺ and HCO₃⁻ ions in choroid plexus epithelial cells.⁸ In addition, HCO₃⁻ is pulled from plasma into the epithelium by Na⁺-coupled HCO₃⁻ transport.²⁹ On accumulation, the HCO₃⁻ is available for release across the CSF-facing membrane by two mechanisms. Through one, HCO₃⁻ in the epithelium diffuses downhill through an anion channel into CSF.³⁴ By another putative route, HCO₃⁻ is transferred by an electrogenic Na⁺-coupled HCO₃⁻ cotransporter at the apical membrane.²⁸^,³⁵ HCO₃⁻-rich nascent CSF reflects facilitated movement of this anion into ventricles as CSF is produced.³⁶

Water

CSF is 99% water. The watery medium of CSF enables multiple buffering, distributive, and excretory functions.¹ Therefore, it is important to thoroughly characterize water movement across the blood-CSF interface. After Na⁺, Cl⁻, and HCO₃⁻ transport into CSF, water chases these osmotically active ions into the ventricles by diffusing down its chemical potential gradient through aquaporin 1 (AQP1) channels in the apical membrane.³⁷ AQP1 channel involvement in CSF formation is deduced from AQP1 knockout mice displaying substantially reduced fluid movement into the ventricles.³⁸ As a result, ICP is lowered.³⁹ Transcellular water diffusion across the choroid plexus is potentially a drug target in modulating CSF dynamics.

Regulation of Cerebrospinal Fluid Formation

CSF formation rate adjusted downward or upward is relevant to management of CSF disorders, such as elevated ICP and ventriculomegaly.²^,⁴⁰ Manipulation of choroid plexus ion transporters and channels is the key to achievement of finer control of epithelial fluid output. From a cellular physiology standpoint, there are multiple loci where CSF formation can be regulated. Two main targeting sites or strategies attempt to modulate choroid plexus secretory function: (1) manipulation of the concentrations of neurotransmitter and neuropeptide ligands that have receptors on choroid epithelial membranes that interface with the extracellular fluid and (2) use of diuretic-type agents to interfere with membrane-bound transporter proteins that effect ion-water fluxes. Many studies focus on reduction of CSF formation because both nature and clinicians try to prevent rises in ICP.

Neurohumoral Ligands and Receptors

Apical and basolateral membranes of choroid plexus contain receptors for biogenic amines and fluid-regulating peptides. Neurogenic tone on CSF formation is commonly inhibitory in nature.⁴¹ Adrenergic regulation of choroid plexus epithelium is substantial, including modulation of the activities of Na⁺,K⁺-ATPase and carbonic anhydrase. The superior cervical ganglion innervates the lateral ventricle choroid plexuses. Sympathetic nerve stimulation or resection, respectively, decreases or increases CSF production by 30%.⁴² Pharmacologic and biochemical evidence indicates that sympathomimetic lowering of CSF formation results from a combined β-receptor inhibition of epithelial secretion and α-receptor stimulation (vasoconstriction and reduced plexus blood flow).⁴¹ Cholinergic agents exogenously administered also decrease CSF production, indicating muscarinic receptor inhibition of the choroid plexus. Both sympathetic and parasympathetic tone autonomically regulate CSF formation.

Serotonin 5-HT_2C receptors in choroid plexus are highly expressed and therefore widely used in pharmacologic investigations,⁴³ including those of CSF formation. Serotonin and serotoninergic agonists perfused through the ventricles reduce CSF production.⁴⁴ Localization of 5-HT_2C receptors to choroid plexus apical membrane points to control of CSF formation by centrally released serotonin. CSF serotonin derived from 5-HT fibers coursing through the ependymal wall⁴⁵ is a potential source of biogenic amine released into the ventricles for convection to the choroid plexus. Such binding of 5-HT to choroid plexus apical receptors would inhibit CSF formation.

Fluid-modulating peptides such as arginine vasopressin (AVP), angiotensin II, and atrial natriuretic peptide (ANP) reduce CSF formation when they are exogenously placed on the ventricular side. This fits with central neuroendocrine-like control of CSF mediated by receptors for these neuropeptides at the apical membrane.² Moreover, the CSF concentration of many neuropeptides, including AVP and ANP, is regulated independently of plasma. This implies neuroendocrine regulation of CSF dynamics by stimulation of receptors at the central or apical side of the choroid plexus.

Peptides figure prominently in transport, permeability, and synthetic and modulatory phenomena at the blood-CSF interface.⁴⁶^,⁴⁷ Neuropeptide regulation of choroid plexus fluid output helps adjust ICP elevation. Both AVP and ANP induce dark, neuroendocrine-type choroid epithelial cells that inhibit CSF production, especially in hydrocephalus.⁴⁸^,⁴⁹ AVP modulation of CSF formation includes complex functional interactions in the choroid plexus with basic fibroblast growth factor⁵⁰ and angiotensin II.⁵¹ AVP directly inhibits epithelial ion transport and constricts choroid plexus vessels, thereby reducing choroidal blood flow, which can be rate limiting for CSF formation.

ANP is the focus of substantial interest in the peptidergic control of CSF dynamics. Autoradiographic mapping of choroid plexus binding sites provides solid evidence for plasticity of ANP receptors ⁴⁹ in response to hydrocephalus and CSF fluid shifting (as in space flight). In humans, the ANP concentration in CSF is independent of plasma levels⁵² and rises in proportion to increments in ICP.⁵³ Interestingly, intracerebroventricular ANP reduces the CSF formation rate in animal models⁵⁴ in the face of increasing plexus blood flow. Systemically, ANP unloads expanded plasma volume by inducing natriuresis. ANP may also unload CSF excess. ANP thus deserves more attention in the CNS as a regulator of CSF pressure and volume by feedback servomechanistic effects on ion transport (through cGMP) and fluid production by the choroid plexus.

Diuretic Agents and Ion Transporters

Both weak and high-ceiling diuretics reduce CSF production. The strategy is to suppress fluid formation without altering CSF composition by interfering with choroid plexus ion transporters at apical or basolateral membranes. One desirable clinical outcome is to lower ICP pressure by decreasing fluid input to the ventricles. To interpret hydrophilic drug effects, a significant factor is whether the inhibiting agent is administered on the blood side (intravenously or intraperitoneally) or the CSF side (intracerebroventricularly). Tight junctions between choroid epithelial cells limit penetration of water-soluble agents by diffusion across the blood-CSF barrier. Hydrophilic agents such as ouabain, a potent inhibitor of apical Na⁺,K⁺-ATPase, therefore do not inhibit CSF formation when they are presented on the blood side of the barrier.⁷ Drug access to the transporter target is critical.

Dual apical transporter targets are the Na⁺ pump and the Na⁺-K⁺-Cl⁻ cotransporter. Directly inhibited Na⁺ pumping is accomplished with cardiac glycosides. Intraventricular ouabain reduces CSF formation,⁵⁵ but it elevates the CSF K⁺ concentration⁷ and is not therapeutically feasible. Digoxin, more lipid soluble, permeates the blood-CSF barrier to reach target sites at the CSF. Patients treated with digoxin have a decline in CSF formation of about 25%.⁵⁶ Geriatric patients receiving digoxin may have a neurotoxicity risk due to reduced CSF turnover added to an already low baseline CSF production in senescence.¹⁸ Another apical target is Na⁺-K⁺-Cl⁻ cotransport, which is bumetanide sensitive.⁵⁷ Bumetanide acts on the kidney to reduce swelling and fluid retention. It has also been tested on the choroid plexus, the “kidney” of the CNS.¹⁹ When it is presented intraventricularly (0.1 mM) in dogs, bumetanide curtails CSF production up to 50%.⁵⁸ Bumetanide administered intravenously, however, affects CSF formation negligibly,⁵⁹ presumably because of poor systemic access to choroid plexus apical membrane. Furosemide, another high-ceiling diuretic, also reduces CSF formation and ICP.⁶⁰ At high doses, furosemide alters choroid plexus blood flow and carbonic anhydrase activity as well as Na⁺-K⁺-Cl⁻ cotransport. A third pharmacologic target on the CSF-facing membrane is the Na⁺-HCO₃⁻ cotransporter.³⁵ Awaiting elucidation is the role of this HCO₃⁻ cotransporter in CSF formation as well as the use of novel agents to access it after systemic administration.

Basolateral membrane targets for choroid plexus fluid production are the Na⁺-H⁺ (NHE) and Cl⁻-HCO₃⁻ (AE) exchangers as well as newly identified HCO₃⁻-loading transporters. Amiloride, a diuretic agent, inhibits Na⁺-H⁺ exchange, but relatively high doses are needed to lower CSF formation rate.⁶¹ Acetazolamide, used clinically to suppress CSF formation,⁶² indirectly slows Na⁺-H⁺ exchange by reducing availability of cellular protons for basolateral exchange with interstitial Na⁺.⁸ With regard to Cl⁻-HCO₃⁻ exchange, the disulfonic stilbene agent DIDS interferes with Cl⁻ uptake by the choroid plexus and reduces CSF formation,⁶³ but its experimental use is complicated by ion-CO₂ imbalances in the periphery. Recently delineated expressions of HCO₃⁻-loading transporters on the plasma side of the choroid plexus epithelium⁶⁴^,⁶⁵ need to be assessed physiologically in relation to CSF dynamics. Finer pharmacologic control of fluid formation⁴⁰ promotes better management of disease-induced changes in CSF pressure, volume, and flow.²

Cerebrospinal Fluid Formation Rate in Hydrocephalus

Structurally and functionally, the choroid plexus is markedly altered in hydrocephalus.⁴⁸ There is a decrease in choroidal solute fluxes⁶⁶^–⁶⁸ and CSF formation rate¹²^,⁴⁹ in congenital and adult chronic hydrocephalus, which is in response to augmented CSF volume and pressure. Reduced choroid plexus blood flow, epithelial cell shrinkage or damage, and diminution of blood-CSF surface area for transport contribute to reduced fluid turnover in hydrocephalus.⁴⁸^,⁶⁶^,⁶⁹

Two non–mutually exclusive mechanisms, physical and physiologic, explain how elevated CSF pressure reduces fluid formation by the choroid plexus.

1 Physically, the rise of ventricular pressure in hydrocephalus opposes and thereby decreases net fluid filtration across the plexus capillaries,⁷⁰ the initial step in CSF formation. This physical factor by Starling’s law reduces fluid (water, ions, and other substrates) availability to the plasma-facing membrane of the choroid plexus. Consequently, as the choroidal perfusion pressure gradient (mean arterial blood pressure minus ICP) is lowered, the plasma ultrafiltrate feeding CSF formation is compromised by the reduced hydrostatic pressure gradient across capillary walls.

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