Cerebrospinal fluid hypersecretion in pediatric hydrocephalus

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Hydrocephalus, despite its heterogeneous causes, is ultimately a disease of disordered CSF homeostasis that results in pathological expansion of the cerebral ventricles. Our current understanding of the pathophysiology of hydrocephalus is inadequate but evolving. Over this past century, the majority of hydrocephalus cases has been explained by functional or anatomical obstructions to bulk CSF flow. More recently, hydrodynamic models of hydrocephalus have emphasized the role of abnormal intracranial pulsations in disease pathogenesis. Here, the authors review the molecular mechanisms of CSF secretion by the choroid plexus epithelium, the most efficient and actively secreting epithelium in the human body, and provide experimental and clinical evidence for the role of increased CSF production in hydrocephalus. Although the choroid plexus epithelium might have only an indirect influence on the pathogenesis of many types of pediatric hydrocephalus, the ability to modify CSF secretion with drugs newer than acetazolamide or furosemide would be an invaluable component of future therapies to alleviate permanent shunt dependence. Investigation into the human genetics of developmental hydrocephalus and choroid plexus hyperplasia, and the molecular physiology of the ion channels and transporters responsible for CSF secretion, might yield novel targets that could be exploited for pharmacotherapeutic intervention.

ABBREVIATIONSAE2 = anion exchanger 2; AQP = aquaporin; BIF = brain interstitial fluid; CA = carbonic anhydrase; CPC = choroid plexus cauterization; CPE = choroid plexus epithelium; CPH = choroid plexus hyperplasia; CPP = choroid plexus papilloma; ETV = endoscopic third ventriculostomy; EVD = external ventricular drain; KCC = K+-Cl− cotransporter; NBCe2 = Na+-HCO3− cotransporter; NCBE = Na+-HCO3− exchanger; NKCC1 = Na+-K+-2Cl− cotransporter; SPAK = Ste20/SPS1-related proline-alanine-rich protein kinase.

Abstract

Hydrocephalus, despite its heterogeneous causes, is ultimately a disease of disordered CSF homeostasis that results in pathological expansion of the cerebral ventricles. Our current understanding of the pathophysiology of hydrocephalus is inadequate but evolving. Over this past century, the majority of hydrocephalus cases has been explained by functional or anatomical obstructions to bulk CSF flow. More recently, hydrodynamic models of hydrocephalus have emphasized the role of abnormal intracranial pulsations in disease pathogenesis. Here, the authors review the molecular mechanisms of CSF secretion by the choroid plexus epithelium, the most efficient and actively secreting epithelium in the human body, and provide experimental and clinical evidence for the role of increased CSF production in hydrocephalus. Although the choroid plexus epithelium might have only an indirect influence on the pathogenesis of many types of pediatric hydrocephalus, the ability to modify CSF secretion with drugs newer than acetazolamide or furosemide would be an invaluable component of future therapies to alleviate permanent shunt dependence. Investigation into the human genetics of developmental hydrocephalus and choroid plexus hyperplasia, and the molecular physiology of the ion channels and transporters responsible for CSF secretion, might yield novel targets that could be exploited for pharmacotherapeutic intervention.

Hydrocephalus is a heterogeneous group of conditions, an overarching feature of which is disordered CSF homeostasis, which typically leads to an abnormal dilation of the cerebral ventricles (i.e., ventriculomegaly) that is often associated with increased intracranial pressure.71 In children, hydrocephalus is anatomically and mechanistically complex; as a consequence, there are multiple overlapping classification schemes that complicate its treatment by neurosurgeons and its investigation by scientists.128 Symptoms depend on the age of onset; infants usually present with progressive macrocephaly, whereas older children present with symptoms of intracranial hypertension.71 Hydrocephalus can disrupt brain development and lead to deficits in cognition and motor and sensory function.111 If untreated, hydrocephalus can cause brain herniation and death.

Hydrocephalus is a common cause of childhood morbidity and death and imposes a major financial burden on the US health care budget.12 The treatment of hydrocephalus is focused on relieving the symptoms it causes, which often includes the placement of ventriculoperitoneal shunts that are subject to frequent failure and surgical revision.12 Despite its prevalence and significance, the pathophysiology of hydrocephalus is poorly understood, and treatment options have not changed significantly in decades.87 Evidence indicates that genetic factors play a major role in the pathogenesis of congenital hydrocephalus,78 and although results of animal studies have contributed to our understanding of the disease,87 our knowledge of the genetic determinants and molecular mechanisms of most types of pediatric hydrocephalus, especially developmental (i.e., congenital) hydrocephalus, is primitive.

For the past century, the standard bulk flow model of CSF physiology was the paradigm used most commonly to explain the pathogenesis of hydrocephalus.30 In this model, CSF is secreted by the choroid plexus in the cerebral ventricles, flows from the lateral ventricles to the third and fourth ventricles, exits the fourth ventricle via the foramina of Luschka and Magendie into the subarachnoid space, circulates around the cerebral convexity and spinal cord, and is absorbed into the cerebral venous system by the arachnoid granulations. According to this scheme, hydrocephalus results from obstruction to CSF flow anywhere along this pathway. More recently, in an alternative hydrodynamic model of hydrocephalus, the role of abnormal intracranial pulsations in disease pathogenesis is emphasized10,37,50,131 and better accounts for observations that are inconsistent with the bulk flow model, including the following: 1) functional arachnoid granulations are not present in children younger than 2 years;8,98 2) the ependyma and sites other than the choroid plexus might account for a significant amount of CSF production;89 3) increasing intraventricular CSF osmolality is sufficient to cause experimental hydrocephalus;79 and 4) despite unobstructed flow and normal mean CSF pressures, increasing intraventricular fluid pulsation amplitudes alone are sufficient to cause hydrocephalus.36,131,132

Most types of pediatric hydrocephalus are characterized ultimately by an abnormal accumulation of CSF. Despite this fact, it is surprising that the role of CSF secretion in the pathogenesis of hydrocephalus has been neglected. Nonetheless, pharmacological (e.g., acetazolamide) and surgical (e.g., choroid plexus cauterization [CPC]) strategies that decrease CSF production have been shown to be successful for specific hydrocephalus subtypes.17,109 Here, we review the physiological and molecular mechanisms of CSF secretion by the choroid plexus and provide evidence for the role of increased CSF production in animal models and children with hydrocephalus. We propose that CSF hypersecretion is probably an underrecognized mechanism of hydrocephalus in at least certain pediatric hydrocephalus subtypes. We suggest that improved knowledge of the molecular physiology of choroid plexus ion-transport pathways and the regulatory mechanisms that control the rate of CSF secretion might uncover targets that could be exploited in novel pharmacotherapeutic strategies for treating hydrocephalus.

Mechanisms of CSF Secretion

The choroid plexus is a highly vascularized network of fenestrated capillaries surrounded by polarized cuboidal epithelial cells connected via tight junctions.28,34,114,122 Unlike the blood-brain barrier, which is formed by tight junctions of cerebral endothelia, the blood-CSF barrier is formed by the tight junctions between choroid plexus epithelial cells (Fig. 1).28,29 The fenestrated capillaries of the choroid plexus are leaky and, in contrast to cerebral endothelia, readily allow the passage of ions and other small molecules.5,121,124,146

FIG. 1.
FIG. 1.

Model for CSF secretion by the CPE; AE2 and NCBE, at an Na/Cl/HCO3 ratio of 18:15:3, transports ions taken up from the basolateral membrane (blood) side into choroid plexus epithelial cells. A large fraction of the Cl and HCO3 influx is recycled across the basolateral membrane. At the luminal (ventricular) side, the Na+/K+-ATPase extrudes most of the Na+. A small contribution to luminal Na+ extrusion is made by NBCe2, which cotransports HCO3. The K-Cl cotransporter, KCC4, a genetic relative of the bumetanide-sensitive Na+-K+-2Cl cotransporter, NKCC1 (see below), which is inhibited by furosemide, secretes the majority of Cl into the CSF lumen. KCC4 is also a main pathway of luminal K+ recycling, which is required for sustained CSF secretion. A fraction of the Na+ extruded into the CSF must reenter the cell via NKCC1 to keep the stoichiometry of the secreted ions to an approximate Na/Cl/HCO3 ratio of 18:15:3. This Na-recycling mechanism is accompanied by extrusion of the imported K+ and Cl via their respective apically expressed ion channels. Because its driving force is close to equilibrium, NKCC1 can mediate the bidirectional transport of ions depending on ion gradients between the blood and CSF. In addition, NKCC1 is highly regulated by SPAK, which in turn is sensitive to changes in intracellular Cl levels and other stimuli, such as osmotic stress and inflammation. It should be noted that ion gradients generated by the primary active Na+/K+-ATPase, which directly pumps out net solute to the CSF, also powers the transcellular movement of ions via the aforementioned Na+- and K+-coupled cotransporters and exchangers. Net ion movement from the blood side to the CSF side creates a small osmolarity difference between these 2 compartments. Water is subsequently “dragged” via osmotic forces across the epithelium and traverses the apical membrane of the choroid plexus epithelial cell through AQP1 in both the luminal and basolateral membranes.

The choroid plexus was first suggested as a site of CSF secretion by Faivre in 185441 and by Cushing in 1914,25 and in 1960, De Rougemont et al.33 provided the first direct experimental evidence of choroid plexus–dependent CSF secretion. Although the theory is controversial, according to most models, the choroid plexus epithelium (CPE) generates a significant fraction, if not the majority, of CSF. Most recent estimates have indicated that the CPE generates approximately 80% of CSF, whereas the remaining 20% is derived from brain interstitial fluid (BIF).13 The CPE is among the most efficient secretory epithelia in the human body; it produces CSF at a rate of 0.4 mL/minute per gram of tissue, a secretion rate that is rivaled only by the proximal tubule of the kidney and the ducts of the exocrine pancreas.28

The total volume of CSF in the entire human CNS (i.e., within the cerebral ventricles and the subarachnoid spaces) is approximately 150 ml; however, it is estimated that 500–600 ml are produced every 24 hours. Thus, CSF volume is replaced 3–4 times per day, and if pathways to CSF reabsorption are blocked or compromised, CSF will accumulate rapidly and the ventricles will expand, which raises an obvious question: where and how is CSF reabsorbed? Classical teaching is that the arachnoid granulations perform this function; however, many of the animal models in which hydrocephalus is studied98,126 and young children7 do not seem to have functional arachnoid granulations. This realization highlights the presence of additional players that influence the delicate balance of CSF homeostasis. As mentioned already, BIF contributes to approximately one-fifth of total CSF production.13 It was recognized recently that the flow of BIF is dynamic; it follows a preferentially perivascular route and traverses the complex microanatomy of the Virchow-Robin space.1,13 Evidence shows that the flow of BIF is not unidirectional and can contribute to both net CSF production and reabsorption. Hence, there is constant exchange between BIF and CSF.66 The constituents of this dynamic mechanism have been called the “glymphatic system.”

The literature presents this system most often as a paravascular route that facilitates the movement of subarachnoid CSF into BIF and then out through the deep draining veins.61,62 These paravascular channels are bound by astrocytic end feet containing aquaporin 4 (AQP4)60 that, when dysfunctional, can contribute to or exacerbate the development of hydrocephalus.60 In other words, it is depicted predominantly in the mammalian CNS as a route of CSF reabsorption. However, the influence of this system as a route for transependymal, extracellular movement of water into CSF spaces, contributing to net CSF production, must not be ignored and should be interpreted as an additional factor that influences therapeutic interventions aimed at controlling alterations in CSF homeostasis. Moreover, the role of the glymphatic system in adaptation of CSF secretion when other parts of the system (i.e., the choroid plexus) have been manipulated, either surgically or medically, is still unknown.

The choroid plexus has the highest rate of ion and water transport of any epithelium in humans.28,82 Secretion of CSF is achieved through the net transport of solutes (Na+, Cl, and HCO3, along with the recycling of K+) across the CPE into the ventricles across the apical and basolateral membranes of the CPE.114 Net transcellular solute influx results in a transepithelial osmotic gradient that favors osmotically driven transcellular movement of water across the CPE. Na+ and Cl are quantitatively the most important ions involved in CSF secretion, and the overall process of CSF secretion is known to depend highly on HCO3. It is currently unclear what role the paracellular route of ion movement, primarily that of Na+, has in CSF secretion.29,114,124 Unlike in most secretory epithelia, tight junctions between choroid plexus epithelial cells resist the movement of Na+ and water, which suggests that CSF secretion is primarily a transcellular process.124 It is interesting to note that the final solute concentrations within the CSF are regulated carefully, and they remain relatively stable even when plasma concentrations vary and demonstrate tight regulation of ion transport.28,29,114,124 The individual channels and transporters involved in ion and water transport required for CSF secretion have not been cataloged completely, but several are of known importance.28 On the basolateral membrane, anion exchanger 2 (AE2) and Na+-HCO3 exchanger NCBE drive the movement of Na+, Cl, and HCO3 from the blood into the CPE. On the luminal membrane, Na+/K+-ATPase, Na+-K+-2Cl cotransporter (NKCC1), Na+-HCO3 cotransporter (NBCe2), the K+-Cl and cotransporter 4 (KCC4, a relative of NKCC1), and K+ and Cl channels coordinate the transport of Na+, K+, Cl, and HCO3 into the CSF and recycle ions back into the CPE.

The luminal membrane of choroid plexus epithelial cells has high water permeability,99 and passive transcellular movement of water from blood to the ventricles is mediated largely through AQP1.95 Permeability of the CPE is reduced by 80% in cells from AQP1 knockout mice.99 It should be emphasized, however, that high AQP1 expression itself does not confer an increase in the secretory capacity of the CPE, because water movement requires a driving force (as mentioned earlier), and basolateral water entry (the mediators of which are not well defined) can be rate limiting. Aquaporins other than AQP1 might be expressed in the choroid plexus basolateral membrane.

The transport of Na+ across the luminal membrane of the CPE is achieved largely by Na+/K+-ATPase.2,44 Several studies that inhibited Na+/K+-ATPase with ouabain on the luminal side of the CPE found a decrease in CSF production.49,57 These results suggest that Na+ flux is a primary driver of CSF secretion and that the Na+/K+-ATPase is integral for maintaining the osmotic and electrochemical gradient required for CSF secretion.49,57 Carbonic anhydrases (CAs) are a large family of enzymes that convert H2O and CO2 into H+ and HCO3, which provides the HCO3 needed for Na+/HCO3 cotransport, a key step in maintaining electroneutrality across the blood-CSF barrier. Studies have found the presence of CAII and CAIII in human and murine CPE.69,123 Partial reduction of CSF secretion by pharmacological inhibition of CA by acetazolamide highlights the importance of this enzyme in CSF homeostasis.17,130

NKCC1 is highly expressed in the luminal (apical) membrane of the CPE.13 In most secretory epithelia, NKCC1, the Na+/K+-ATPase, and K+ channels are located on the basolateral membrane, and Cl channels are located on the apical membrane.28,29,114,124 The CPE is unique and exhibits the opposite polarity in the expression of these transporters, which creates a slight net positive electrochemical gradient and makes Na+ movement an active energy-dependent process that occurs primarily through transcellular mechanisms.28,29,114,124 The stoichiometric coupling and directionality of the cations and Cl ions translocated by NKCC1 results in an electrically silent (i.e., electroneutral) secondarily active transport process that is energetically driven by transmembrane Na+ and K+ gradients established by Na+/K+-ATPase. NKCC1 is inhibited by bumetanide and, to a much lesser extent, by furosemide.116 Similar to NKCC1, the KCCs are inhibited by furosemide; however, bumetanide inhibits the KCC cotransporters 1000 times less potently than NKCC1.116 The driving force for NKCC1 in choroid plexus epithelial cells is close to equilibrium, given the relatively low K+ concentration of CSF and high intracellular concentration of Na+. Consistent with this fact, there is evidence that NKCC1 mediates both outward-directed (into the CSF lumen) and inward-directed ion transport.75,107,147 Because the ion composition of CSF is tightly regulated and maintained,58,94,114 the bidirectional ion movement via NKCC1 might enable it to respond dynamically to physiological changes in the CSF to maintain homeostasis. In other secretory epithelia, the Ste20/SPS1-related proline-alanine-rich protein kinase (SPAK) associates with NKCC1 via a CCT-binding module in SPAK and a (R/K)FX(V/I)-binding motif in NKCC1105 and stimulates NKCC1 via direct phosphorylation at Thr-203/Thr-207/Thr-212.9,72 The importance of SPAK in the dynamic regulation of NKCC1 in renal,47,48 intestinal,47,148 and pancreatic47,101 epithelia is well documented. However, a potential role in the CPE for SPAK-NKCC1–mediated regulation has not been well studied.

The upstream mechanisms that regulate the rate of production and the composition of CSF are less well known.23,28,110 However, many of the important hormones and their receptors that regulate systemic NaCl and water homeostasis, including aldosterone, angiotensin II, and vasopressin, are expressed in the CPE and ependyma also and likely play local roles in the CPE with respect to CSF production and brain extracellular fluid-volume regulation.

Hydrocephalus and CSF Production

The rates of CSF production and reabsorption must be in equilibrium. Disturbances in homeostasis can lead to hydrocephalus that results from CSF hypersecretion secondary to choroid plexus hyperplasia (CPH)4 or non-obstructive tumors of the choroid plexus, such as choroid plexus papilloma (CPP),11 which are rare causes of pediatric hydrocephalus. In the literature, CPH is also referred to as diffuse villous hyperplasia of the choroid plexus or villous hypertrophy.4 The difference between hyperplasia and hypertrophy of the choroid plexus is not always stated explicitly; therefore, for the purposes of this review, cases of CPH, diffuse villous hyperplasia of the choroid plexus, and villous hypertrophy will be referred to as cases of CPH.

Choroid plexus papilloma is a rare intracranial tumor that accounts for 1%–4% of all pediatric brain tumors.35,52 It is a distinct mass that is separate from the CPE and often presents within the first 2 years of life. Choroid plexus hyperplasia is a rare congenital disorder that causes the CPE to become enlarged and hypersecrete CSF, typically by an increase in the number of normal choroid plexus epithelial cells. The diagnosis of hydrocephalus with CPP and CPH origin is critical, because the standard treatment is not a shunt procedure but, rather, resection of the tumor or excessive CPE.4,27,45 The initial diagnosis of CPP or CPH has been difficult historically, especially before imaging techniques such as MRI.27,55 In general, the diagnosis is made after shunt failure or the development of ascites, which prompts a revision or externalization of the shunt. If the shunt is externalized, the external ventricular drain (EVD) illuminates the excessive rate of CSF production, which leads to a diagnosis.

To date, 27 cases of CPP21,35,38–40,46,51,52,90,96,102,103,113,149 and CPH3,4,14,20,27,45,55,56,64,104,123,142,143 have been reported to be associated with nonobstructive hydrocephalus; the rates of CSF hypersecretion were reported for 19 of those cases (Table 1). Normal production of CSF is approximately 500 ml/day26; however, in the setting of CPP or CPH, CSF secretion rates were reported to be up to 5000 ml/day, and higher rates correlated with more severe hydrocephalus (Table 1).3,4,14,18,20,27,38,40,46,55,56,90,96,102,117,123,127 After surgical intervention (e.g., CPC or tumor removal), the rates of CSF production decreased,4,20,35,46,51,90,96,117 and in some cases, there was no further need for a shunt.27,51,56 In addition to CPP and CPH, overproduction of CSF contributing to hydrocephalus has also been implicated in idiopathic intracranial hypertension,59 infectious hydrocephalus,16 and intraventricular hemorrhage–associated hydrocephalus,126 but secretion rates in the patients with these conditions have not been well documented.

TABLE 1.

Case reports of hydrocephalus associated with CSF hypersecretion

PathologyAge & SexCSF Secretion (ml/24 hrs)Method of MeasurementAuthors & Year
CPP10 days, F800–1000EVDDi Rocco & Iannelli, 1997
5 mos, F2000*VLPEisenberg et al., 1974
15 mos, F400–960EVDFairburn, 1960
10 mos, M2000EVDFujimura et al., 2004
3.5 yrs, F2280*EVDGudeman et al., 1979
23 mos, M1500*VLPMilhorat et al., 1976
6 mos, F3200–5000EVDNimjee et al., 2010
8 mos, F1400–1500EVDPawar et al., 2003
2 yrs, M900–1200EVDPawar et al., 2003
22 mos, F800–1500EVDSaito et al., 2014
CPH8 mos, F1500EVDAnei et al., 2011
11 yrs, M4200*EVDAziz et al., 2005
3 mos, M900EVDBritz et al., 1996
9 days, M2000EVDCataltepe et al., 2010
7 mos, F1200EVDD'Ambrosio et al., 2003
3 yrs, F2000EVDHallaert et al., 2012
7 yrs, F2000EVDHirano et al., 1994
15 mos, F1400EVDSmith et al., 2007
24 mos, F2000EVDTamburrini et al., 2006
Unknown2.5 yrs, NA2000*EVDCasey & Vries, 1989

NA = not available; VLP = ventriculolumbar perfusion.

Value (originally reported in milliliters per minute or milliliters per hour) was extrapolated to be presented here in milliliters per 24 hours.

From a molecular physiology perspective, many solute-(ion channel and transporters) and water-transport (AQP) pathways of the choroid plexus have been implicated in the pathogenesis of hydrocephalus in humans and in animal models.24,43,53,63,67,100,108,112,120,129,145 For example, AQP4 is expressed in glia and ependymocytes, and a subset of AQP4 knockout mice develop severe obstructive hydrocephalus as a result of total obstruction of the cerebral aqueduct.42 In contrast, ependymal AQP4 is upregulated in the late stages of hydrocephalus, possibly as a compensatory mechanism to maintain water homeostasis.19,86 In addition, it has been well documented that the ependymal cells lining the ventricular space have motile cilia and that defects in motile cilia lead to hydrocephalus.6,84 Mice with mutations in the cilia proteins Spag6 or hydin, or the transcription factor Hfh4 (Foxj1, Mouse Genome Informatics) that lack ependymal cell cilia all exhibit hydrocephalus.22,32,118 Cilia function in the CSF ventricular system is also important in humans, as evidenced by the incidence of hydrocephalus in human patients with primary ciliary dyskinesias.15 Data from hydrocephalic murine E2F-5 and Tg737orpk mutants support a model in which cilia dysfunction leads not only to disrupted ependymal cilia-generated CSF flow but also elevated intracellular cyclic adenosine monophosphate (cAMP) levels, an increased Cl concentration in the CSF, and a marked increase in CSF production.6,84 Altogether, these data suggest that cilia function is necessary for regulating ion transport and CSF production, as well as CSF flow through the ventricular system.

Medical Management of Hydrocephalus by Targeting CSF Production

Knowledge of the molecular mechanisms of CSF secretion, although incomplete, has improved over the past few decades. As a direct result of this knowledge, pharmacological disruption of these mechanisms as a means of modulating CSF secretion has become commonplace. Diuretics are, by far, the drugs used most commonly for this purpose. However, these drugs are often ineffective, have adverse effects, and have off-target effects in the kidney.

Acetazolamide, a CA inhibitor, has been shown to lead to an approximately 30%–60% decrease in CSF rate and daily output.17,74,88,93 As reviewed earlier, the charge gradient created by transport of positive ions (primarily Na+) into the ventricular space is balanced by the cotransport of bicarbonate, which is produced by CA in the intracellular compartment. However, the precise mechanism by which acetazolamide reduces CSF production is not completely understood. The partial effect of this inhibitor might be explained by the presence of acetazolamide-insensitive CAIII, which has been found in humans and in animal models.97

Loop diuretics have also been used in an attempt to mitigate the effects of CSF hypersecretion. Bumetanide (an NKCC1 inhibitor) and furosemide (a KCC inhibitor), alone or in combination with acetazolamide, have been documented to decrease CSF production in canine and feline models.65,70 The effect of bumetanide on CSF production, in conjunction with its selectivity for NKCC1, highlights the importance of this transporter in CSF homeostasis. Animal evidence also reveals the effect of furosemide in disrupting ion transport across the blood-CSF barrier, which reduces the rate of CSF secretion.68,85 Because the effects of these drugs were also observed in animals that underwent a nephrectomy, potential secondary diuretic or hemodynamic effects caused by renal electrolyte imbalance, including the development of acid-base disturbances, are unlikely to explain the decrease in CSF production.88,115

Despite theoretical effectiveness and encouraging results from animal models, a randomized controlled trial in which parenteral administration of a combination of acetazolamide and furosemide was used in patients with posthemorrhagic hydrocephalus (n = 177) found that the drugs led to a higher rate of shunt placement and an increase in neurological morbidity (auditory) in the cohort.63,76 A smaller trial (n = 16 patients) performed shortly thereafter that involved administering intravenous acetazolamide plus furosemide versus serial lumbar puncture in preterm infants with posthemorrhagic hydrocephalus found that 9 of 10 infants who received the drug combination avoided shunt placement, whereas only 3 of 6 assigned to serial LPs experienced the same result. However, the authors reported that a significant proportion of the infants developed nephrocalcinosis as a result of pharmacotherapy.83 A systematic Cochrane review, which included both of these trials, reinforced the conclusion that combination therapy with acetazolamide and furosemide is neither effective nor safe in treating posthemorrhagic hydrocephalus.145

In summary, the use of diuretics for pediatric hydrocephalus is severely limited by its low effectiveness in adequately suppressing CSF production when administered enterally or parenterally, which might be because of the poor transcellular passage of these drugs in the CPE and, in the case of furosemide and bumetanide, their inability to reach their target transporters on the apical membrane of the CPE. This limitation is complicated further by a significant adverse-effect profile secondary to their influence on other transport epithelia, primarily in the kidney. In light of these circumstances, it would be very interesting to test the utility of bumetanide administered via an intra-cerebroventricular approach, such as through an EVD or Ommaya reservoir, on CSF secretion and hydrocephalus in humans. These observations also underscore the need for newer and more specific and potent drugs.

Modulation of CSF Secretion by Surgical Intervention of the Choroid Plexus

Operative techniques that involve targeting CSF production have been described in the literature for close to 100 years. Dandy31 described one of the earliest surgical interventions for treating hydrocephalus by means of ablating the choroid plexus. Early results from small series of choroid plexus cauterization alone for hydrocephalus were modest.109,119 A few attempts have been made over the past 3 decades to describe the effect of choroid plexus disruption through either plexectomy or cauterization. A small series of 17 patients with “chronic hydrocephalus” underwent primary choroid plexectomy; the authors reported a 37% success rate, defined as avoidance of CSF-diversion procedures.81 Subsequent small series in selected patients who underwent either CPC or plexectomy found advantages in terms of reduced rates of reoperation, readmission, or operative complications.92,144 The underlying motif for these reports points to adequate patient selection as a key determinant in maximizing the chances of shunt avoidance when performing isolated choroid plexus–disruption procedures.

A single large series, the report for which was published in 1994, included a cohort of 90 children who underwent primary CPC as the single initial intervention for hydrocephalus of multiple etiologies. The group reported that 36% of the patients did not require shunt placement in the mean follow-up period of 10.5 years. It is interesting to note that success rates were higher in patients with communicating hydrocephalus and in those with slow progression of ventriculomegaly,109 which further reinforces the concept that careful patient selection is a key determinant in selecting an adequate surgical approach. This notion probably parallels the pathophysiological diversity of hydrocephalus, which emphasizes the need for better and more precise interventions that deal with the underlying mechanism of disease.

The modern experience with CPC has been in combination with endoscopic third ventriculostomy (ETV), reported initially by Warf134 after extensive experience in Uganda. The ETV-CPC procedure involves using a flexible endoscope and monopolar cautery to coagulate the entire choroid plexus throughout both lateral ventricles. In accordance with the bulk flow model, ETV might bypass obstruction, and CPC might decrease CSF production; according to the hydrodynamic model, ETV might serve as a pulsation absorber, whereas CPC reduces the intraventricular pulsation amplitude.135,138

Compared with ETV alone, ETV-CPC yields superior results in children < 1 year of age134 and in all studied etiological subgroups.136,137,139,141 The efficacy of ETV-CPC is proportional to the amount of choroid plexus cauterized140 and does not negatively affect cognition compared with shunting or ETV alone.133 However, other potential collateral effects of this treatment still remain unknown, including those related to immunological function and neurodevelopment. Based on these promising results in Uganda, ETV-CPC has been introduced in North America and produced favorable results in a single-institution series125 and in a preliminary study through the Hydrocephalus Clinical Research Network.80 In addition to ETV-CPC, preoperative embolization of choroid plexus tumors in children has been shown to decrease CSF production significantly by removing the blood supply of the tumor.54

It is unfortunate that few studies have been conducted to explore the true effect of choroid plexus ablation on CSF production, which clearly relates to the infeasibility of the invasive procedures used to estimate rates of CSF production (e.g., EVD) as a part of long-term patient follow-up. Hence, clinicians are limited by indirect indicators of diminished CSF production after surgical management, such as clinical improvement and/or resolution of ventriculomegaly observed via MRI. More recently, imaging techniques that allow the quantification of remaining choroid plexus or depict the presence of CSF turbulence after ETV-CPC have enhanced clinicians' ability to follow the effectiveness of these interventions.106

The best starting point for answering the true effect of choroid plexus ablation on CSF production comes from observations made by Milhorat et al. in the early 1970s.91 These meticulous studies revealed that choroid plexectomy reduced normal CSF production rates in Rhesus monkeys by an average of only 33%–40%. This result, together with treatment failure in a nonnegligible proportion of patients treated with ETV-CPC (up to 45% of whom required shunt placement within the follow-up period),125,134 highlights the complexity of the pathophysiology of CSF homeostasis. As mentioned earlier, physiological adaptation to a change in the normal production of CSF might imply compensation by the remaining choroid plexus tissue not cauterized in standard endoscopic approaches or by upregulation of secondary mechanisms of secretion, as already mentioned earlier.

Novel Strategies for Targeting CSF Production for the Treatment of Pediatric Hydrocephalus

Despite the high prevalence of hydrocephalus, the molecular mechanism(s) leading to its pathology remains elusive in most cases. Thus, to develop alternative treatment strategies, a better understanding of the pathogenesis of this disease is needed. A 2015 National Institutes of Health–sponsored symposium listed the elucidation of the mechanisms underlying CSF production and the discovery of related drug therapies as top priorities for hydrocephalus research.87 Critical in the effort to develop novel drugs to inhibit CSF secretion is defining the critical regulatory pathways that mediate this process. In any complex physiological process with multiple overlapping regulatory pathways, molecular genetics (both mouse and human) has the power to pinpoint key homeostatic nodes in an unbiased way. Next-generation DNA sequencing of humans with developmental hydrocephalus and of those with CPP or CPH with hydrocephalus, coupled with modeling these disease-causing mutations in mice with CRISPR/CAS gene editing, might help uncover novel mediators and regulators of CSF homeostasis. In addition to CPP and CPH, CSF secretion and ion-transport mechanisms should be studied in other types of hydrocephalus, especially those associated with inflammation, such as infectious hydrocephalus16 and intraventricular hemorrhage–associated hydrocephalus.126 Another important line of investigation is for how to improve the drugs that are directed at known targets of CSF secretion, including NKCC1, AQP1, NCBE, AE2, and the V1a vasopressin receptors. In this regard, drugs capable of rapidly and reversibly inhibiting CSF secretion would be useful for not only acute hydrocephalus but also other neurosurgical conditions associated with high intracranial pressure, including cerebral edema.73,77

Acknowledgments

Dr. Kahle is supported by the March of Dimes, the Simons Foundation, and the National Institutes of Health Centers for Mendelian Genomics.

References

  • 1

    Abbott NJ: Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 45:5455522004

  • 2

    Amin MSReza EWang HLeenen FH: Sodium transport in the choroid plexus and salt-sensitive hypertension. Hypertension 54:8608672009

  • 3

    Anei RHayashi YHiroshima SMitsui NOrimoto RUemori G: Hydrocephalus due to diffuse villous hyperplasia of the choroid plexus. Neurol Med Chir (Tokyo) 51:4374412011

  • 4

    Aziz AAColeman LMorokoff AMaixner W: Diffuse choroid plexus hyperplasia: an under-diagnosed cause of hydrocephalus in children?. Pediatr Radiol 35:8158182005

  • 5

    Ballermann BJStan RV: Resolved: capillary endothelium is a major contributor to the glomerular filtration barrier. J Am Soc Nephrol 18:243224382007

  • 6

    Banizs BPike MMMillican CLFerguson WBKomlosi PSheetz J: Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus. Development 132:532953392005

  • 7

    Bateman GAAlber MSchuhmann MU: An association between external hydrocephalus in infants and reversible collapse of the venous sinuses. Neuropediatrics 45:1831872014

  • 8

    Bateman GABrown KM: The measurement of CSF flow through the aqueduct in normal and hydrocephalic children: from where does it come, to where does it go?. Childs Nerv Syst 28:55632012

  • 9

    Begum GYuan HKahle KTLi LWang SShi Y: Inhibition of wnk3 kinase signaling reduces brain damage and accelerates neurological recovery after stroke. Stroke 46:195619652015

  • 10

    Bering EA Jr: Circulation of the cerebrospinal fluid. Demonstration of the choroid plexuses as the generator of the force for flow of fluid and ventricular enlargement. J Neurosurg 19:4054131962

  • 11

    Bettegowda CAdogwa OMehta VChaichana KLWeingart JCarson BS: Treatment of choroid plexus tumors: a 20-year single institutional experience. J Neurosurg Pediatr 10:3984052012

  • 12

    Boivin MJKakooza AMWarf BCDavidson LLGrigorenko EL: Reducing neurodevelopmental disorders and disability through research and interventions. Nature 527:S155S1602015

  • 13

    Brinker TStopa EMorrison JKlinge P: A new look at cerebrospinal fluid circulation.. Fluids Barriers CNS 11:102014

  • 14

    Britz GWKim DKLoeser JD: Hydrocephalus secondary to diffuse villous hyperplasia of the choroid plexus. Case report and review of the literature. J Neurosurg 85:6896911996

  • 15

    Bush A: Primary ciliary dyskinesia. Acta Otorhinolaryngol Belg 54:3173242000

  • 16

    Cardia EMolina DAbbate FMastroeni PStassi GGermanà GP: Morphological modifications of the choroid plexus in a rodent model of acute ventriculitis induced by gram-negative liquoral sepsis. Possible implications in the pathophysiology of hypersecretory hydrocephalus. Childs Nerv Syst 11:5115161995

  • 17

    Carrion EHertzog JHMedlock MDHauser GJDalton HJ: Use of acetazolamide to decrease cerebrospinal fluid production in chronically ventilated patients with ventriculopleural shunts. Arch Dis Child 84:68712001

  • 18

    Casey KFVries JK: Cerebral fluid overproduction in the absence of tumor or villous hypertrophy of the choroid plexus. Childs Nerv Syst 5:3323341989

  • 19

    Castañeyra-Ruiz LGonzález-Marrero IGonzález-Toledo JMCastañeyra-Ruiz Ade Paz-Carmona HCastañeyra-Perdomo A: Aquaporin-4 expression in the cerebrospinal fluid in congenital human hydrocephalus.. Fluids Barriers CNS 10:182013

  • 20

    Cataltepe OLiptzin DJolley LSmith TW: Diffuse villous hyperplasia of the choroid plexus and its surgical management. J Neurosurg Pediatr 5:5185222010

  • 21

    Ceddia ADi Rocco CCarlucci A: [Hypersecretive congenital hydrocephalus due to choroid plexus villous hypertrophy associated with controlateral papilloma.]. Minerva Pediatr 45:3633671993. (Ital)

  • 22

    Chen JKnowles HJHebert JLHackett BP: Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry. J Clin Invest 102:107710821998

  • 23

    Christensen HLNguyen ATPedersen FDDamkier HH: Na+ dependent acid-base transporters in the choroid plexus insights from slc4 and slc9 gene deletion studies.. Front Physiol 4:3042013

  • 24

    Christensen IBGyldenholm TDamkier HHPraetorius J: Polarization of membrane associated proteins in the choroid plexus epithelium from normal and slc4a10 knockout mice.. Front Physiol 4:3442013

  • 25

    Cushing H: Studies on the cerebrospinal fluid: I. Introduction. J Med Res 31:1191914

  • 26

    Cutler RWPage LGalicich JWatters GV: Formation and absorption of cerebrospinal fluid in man. Brain 91:7077201968

  • 27

    D'Ambrosio ALO'Toole JEConnolly ES JrFeldstein NA: Villous hypertrophy versus choroid plexus papilloma: a case report demonstrating a diagnostic role for the proliferation index. Pediatr Neurosurg 39:91962003

  • 28

    Damkier HHBrown PDPraetorius J: Cerebrospinal fluid secretion by the choroid plexus. Physiol Rev 93:184718922013

  • 29

    Damkier HHBrown PDPraetorius J: Epithelial pathways in choroid plexus electrolyte transport. Physiology (Bethesda) 25:2392492010

  • 30

    Dandy WE: Experimental hydrocephalus. Ann Surg 70:1291421919

  • 31

    Dandy WE: Extirpation of the choroid plexus of the lateral ventricles in communicating hydrocephalus. Ann Surg 68:5695791918

  • 32

    Davy BERobinson ML: Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene. Hum Mol Genet 12:116311702003

  • 33

    De Rougemont JAmes A IIINesbett FBHofmann HF: Fluid formed by choroid plexus a technique for its collection and a comparison of its electrolyte composition with serum and cisternal fluids. J Neurophysiol 23:4854951960

  • 34

    Del Bigio MR: The ependyma: a protective barrier between brain and cerebrospinal fluid. Glia 14:1131995

  • 35

    Di Rocco CIannelli A: Poor outcome of bilateral congenital choroid plexus papillomas with extreme hydrocephalus. Eur Neurol 37:33371997

  • 36

    Di Rocco CPettorossi VECaldarelli MMancinelli RVelardi F: Communicating hydrocephalus induced by mechanically increased amplitude of the intraventricular cerebrospinal fluid pressure: experimental studies. Exp Neurol 59:40521978

  • 37

    Egnor MZheng LRosiello AGutman FDavis R: A model of pulsations in communicating hydrocephalus. Pediatr Neurosurg 36:2813032002

  • 38

    Eisenberg HMMcComb JGLorenzo AV: Cerebrospinal fluid overproduction and hydrocephalus associated with choroid plexus papilloma. J Neurosurg 40:3813851974

  • 39

    Erman TGöçer AIErdoğan STuna MIldan FZorludemir S: Choroid plexus papilloma of bilateral lateral ventricle. Acta Neurochir (Wien) 145:1391432003

  • 40

    Fairburn B: Choroid plexus papilloma and its relation to hydrocephalus. J Neurosurg 17:1661711960

  • 41

    Faivre J: Structure du conarium et des plexus choroide chez l'hommes et des animaux. Gaz Med Paris 9:5555561854

  • 42

    Feng XPapadopoulos MCLiu JLi LZhang DZhang H: Sporadic obstructive hydrocephalus in Aqp4 null mice. J Neurosci Res 87:115011552009

  • 43

    Filippidis ASKalani MYRekate HL: Hydrocephalus and aquaporins: lessons learned from the bench. Childs Nerv Syst 27:27332011

  • 44

    Fisone GSnyder GLFryckstedt JCaplan MJAperia AGreengard P: Na+,K+-ATPase in the choroid plexus Regulation by serotonin/protein kinase C pathway. J Biol Chem 270:242724301995

  • 45

    Fujimoto YMatsushita HPlese JPMarino R Jr: Hydrocephalus due to diffuse villous hyperplasia of the choroid plexus. Case report and review of the literature. Pediatr Neurosurg 40:32362004

  • 46

    Fujimura MOnuma TKameyama MMotohashi OKon HYamamoto K: Hydrocephalus due to cerebrospinal fluid overproduction by bilateral choroid plexus papillomas. Childs Nerv Syst 20:4854882004

  • 47

    Gagnon KBDelpire E: Molecular physiology of SPAK and OSR1: two Ste20-related protein kinases regulating ion transport. Physiol Rev 92:157716172012

  • 48

    Gagnon KBEngland RDelpire E: Volume sensitivity of cation-Cl cotransporters is modulated by the interaction of two kinases: Ste20-related proline-alanine-rich kinase and WNK4. Am J Physiol Cell Physiol 290:C134C1422006

  • 49

    Garg LCMathur PP: Effect of ouabain on cerebrospinal fluid formation after carbonic anhydrase inhibition. Arch Int Pharmacodyn Ther 213:1901941975

  • 50

    Greitz D: Paradigm shift in hydrocephalus research in legacy of Dandy's pioneering work: rationale for third ventriculostomy in communicating hydrocephalus. Childs Nerv Syst 23:4874892007

  • 51

    Gudeman SKSullivan HGRosner MJBecker DP: Surgical removal of bilateral papillomas of the choroid plexus of the lateral ventricles with resolution of hydrocephalus. Case report. J Neurosurg 50:6776811979

  • 52

    Gupta PSodhi KSMohindra SSaxena AKDas AKhandelwal N: Choroid plexus papilloma of the third ventricle: a rare infantile brain tumor. J Pediatr Neurosci 8:2472492013

  • 53

    Hack MCohen AR: Acetazolamide plus furosemide for periventricular dilatation: lessons for drug therapy in children. Lancet 352:4184191998

  • 54

    Haliasos NBrew SRobertson FHayward RThompson DChakraborty A: Pre-operative embolisation of choroid plexus tumours in children. Part II. Observations on the effects on CSF production. Childs Nerv Syst 29:71762013

  • 55

    Hallaert GGVanhauwaert DJLogghe KVan den Broecke CBaert EVan Roost D: Endoscopic coagulation of choroid plexus hyperplasia. J Neurosurg Pediatr 9:1691772012

  • 56

    Hirano HHirahara KAsakura TShimozuru TKadota KKasamo S: Hydrocephalus due to villous hypertrophy of the choroid plexus in the lateral ventricles. Case report. J Neurosurg 80:3213231994

  • 57

    Holloway LS JrCassin S: Effect of acetazolamide and ouabain on CSF production rate in the newborn dog. Am J Physiol 223:5035061972

  • 58

    Husted RFReed DJ: Regulation of cerebrospinal fluid bicarbonate by the cat choroid plexus. J Physiol 267:4114281977

  • 59

    Iencean SM: Simultaneous hypersecretion of CSF and of brain interstitial fluid causes idiopathic intracranial hypertension. Med Hypotheses 61:5295322003

  • 60

    Iliff JJChen MJPlog BAZeppenfeld DMSoltero MYang L: Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 34:16180161932014

  • 61

    Iliff JJLee HYu MFeng TLogan JNedergaard M: Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 123:129913092013

  • 62

    Iliff JJWang MZeppenfeld DMVenkataraman APlog BALiao Y: Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 33:18190181992013

  • 63

    International PHVD Drug Trial Group: International randomised controlled trial of acetazolamide and furosemide in posthaemorrhagic ventricular dilatation in infancy. Lancet 352:4334401998

  • 64

    Iplikcioglu ACBek SGökduman CABikmaz KCosar M: Diffuse villous hyperplasia of choroid plexus. Acta Neurochir (Wien) 148:6916942006

  • 65

    Javaheri SWagner KR: Bumetanide decreases canine cerebrospinal fluid production. In vivo evidence for NaCl cotransport in the central nervous system. J Clin Invest 92:225722611993

  • 66

    Jessen NAMunk ASLundgaard INedergaard M: The glymphatic system: a beginner's guide. Neurochem Res 40:258325992015

  • 67

    Johanson CMcMillan PTavares RSpangenberger ADuncan JSilverberg G: Homeostatic capabilities of the choroid plexus epithelium in Alzheimer's disease.. Cerebrospinal Fluid Res 1:32004

  • 68

    Johanson CEMurphy VADyas M: Ethacrynic acid and furosemide alter Cl, K, and Na distribution between blood, choroid plexus CSF, and brain. Neurochem Res 17:107910851992

  • 69

    Johansson PDziegielewska KSaunders N: Low levels of Na, K-ATPase and carbonic anhydrase II during choroid plexus development suggest limited involvement in early CSF secretion. Neurosci Lett 442:77802008

  • 70

    Johnson DCSinger SHoop BKazemi H: Chloride flux from blood to CSF: inhibition by furosemide and bumetanide. J Appl Physiol 1985. 63:159116001987

  • 71

    Kahle KTKulkarni AVLimbrick DD JrWarf BC: Hydrocephalus in children. Lancet 387:7887992016

  • 72

    Kahle KTRing AMLifton RP: Molecular physiology of the WNK kinases. Annu Rev Physiol 70:3293552008

  • 73

    Kahle KTSimard JMStaley KJNahed BVJones PSSun D: Molecular mechanisms of ischemic cerebral edema: role of electroneutral ion transport. Physiology (Bethesda) 24:2572652009

  • 74

    Karimy JKKahle KTKurland DBYu EGerzanich VSimard JM: A novel method to study cerebrospinal fluid dynamics in rats. J Neurosci Methods 241:78842015

  • 75

    Keep RFXiang JBetz AL: Potassium cotransport at the rat choroid plexus. Am J Physiol 267:C1616C16221994

  • 76

    Kennedy CRAyers SCampbell MJElbourne DHope PJohnson A: Randomized, controlled trial of acetazolamide and furosemide in posthemorrhagic ventricular dilation in infancy: follow-up at 1 year. Pediatrics 108:5976072001

  • 77

    Khanna AWalcott BPKahle KTSimard JM: Effect of glibenclamide on the prevention of secondary brain injury following ischemic stroke in humans. Neurosurg Focus 36:1E112014

  • 78

    Kousi MKatsanis N: The genetic basis of hydrocephalus. Annu Rev Neurosci 39:4094352016

  • 79

    Krishnamurthy SLi JSchultz LMcAllister JP II: Intraventricular infusion of hyperosmolar dextran induces hydrocephalus: a novel animal model of hydrocephalus.. Cerebrospinal Fluid Res 6:162009

  • 80

    Kulkarni AVRiva-Cambrin JBrowd SRDrake JMHolubkov RKestle JR: Endoscopic third ventriculostomy and choroid plexus cauterization in infants with hydrocephalus: a retrospective Hydrocephalus Clinical Research Network study. J Neurosurg Pediatr 14:2242292014

  • 81

    Lapras CMertens PGuilburd JNLapras C JrPialat JPatet JD: Choroid plexectomy for the treatment of chronic infected hydrocephalus. Childs Nerv Syst 4:1391431988

  • 82

    Lehtinen MKBjornsson CSDymecki SMGilbertson RJHoltzman DMMonuki ES: The choroid plexus and cerebrospinal fluid: emerging roles in development, disease, and therapy. J Neurosci 33:17553175592013

  • 83

    Libenson MHKaye EMRosman NPGilmore HE: Acetazolamide and furosemide for posthemorrhagic hydrocephalus of the newborn. Pediatr Neurol 20:1851911999

  • 84

    Lindeman GJDagnino LGaubatz SXu YBronson RTWarren HB: A specific, nonproliferative role for E2F-5 in choroid plexus function revealed by gene targeting. Genes Dev 12:109210981998

  • 85

    Lorenzo AVHornig GZavala LMBoss VWelch K: Furosemide lowers intracranial pressure by inhibiting CSF production. Z Kinderchir 41:Suppl 110121986

  • 86

    Mao XEnno TLDel Bigio MR: Aquaporin 4 changes in rat brain with severe hydrocephalus. Eur J Neurosci 23:292929362006

  • 87

    McAllister JP IIWilliams MAWalker MLKestle JRRelkin NRAnderson AM: An update on research priorities in hydrocephalus: overview of the third National Institutes of Health–sponsored symposium “Opportunities for Hydrocephalus Research: Pathways to Better Outcomes”. J Neurosurg 123:142714382015

  • 88

    McCarthy KDReed DJ: The effect of acetazolamide and furosemide on cerebrospinal fluid production and choroid plexus carbonic anhydrase activity. J Pharmacol Exp Ther 189:1942011974

  • 89

    Milhorat TH: Choroid plexus and cerebrospinal fluid production. Science 166:151415161969

  • 90

    Milhorat THHammock MKDavis DAFenstermacher JD: Choroid plexus papilloma. I. Proof of cerebrospinal fluid overproduction. Childs Brain 2:2732891976

  • 91

    Milhorat THHammock MKFenstermacher JDLevin VA: Cerebrospinal fluid production by the choroid plexus and brain. Science 173:3303321971

  • 92

    Morota NFujiyama Y: Endoscopic coagulation of choroid plexus as treatment for hydrocephalus: indication and surgical technique. Childs Nerv Syst 20:8168202004

  • 93

    Murphy VAJohanson CE: Acidosis, acetazolamide, and amiloride: effects on 22Na transfer across the blood-brain and blood-CSF barriers. J Neurochem 52:105810631989

  • 94

    Murphy VASmith QRRapoport SI: Homeostasis of brain and cerebrospinal fluid calcium concentrations during chronic hypo- and hypercalcemia. J Neurochem 47:173517411986

  • 95

    Nielsen SSmith BLChristensen EIAgre P: Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia. Proc Natl Acad Sci U S A 90:727572791993

  • 96

    Nimjee SMPowers CJMcLendon REGrant GAFuchs HE: Single-stage bilateral choroid plexectomy for choroid plexus papilloma in a patient presenting with high cerebrospinal fluid output. J Neurosurg Pediatr 5:3423452010

  • 97

    Nógrádi AKelly CCarter ND: Localization of acetazolamide-resistant carbonic anhydrase III in human and rat choroid plexus by immunocytochemistry and in situ hybridisation. Neurosci Lett 151:1621651993

  • 98

    Oi SDi Rocco C: Proposal of “evolution theory in cerebrospinal fluid dynamics” and minor pathway hydrocephalus in developing immature brain. Childs Nerv Syst 22:6626692006

  • 99

    Oshio KWatanabe HSong YVerkman ASManley GT: Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1. FASEB J 19:76782005

  • 100

    Papadopoulos MCVerkman AS: Potential utility of aquaporin modulators for therapy of brain disorders. Prog Brain Res 170:5896012008

  • 101

    Park HWNam JHKim JYNamkung WYoon JSLee JS: Dynamic regulation of CFTR bicarbonate permeability by [Cl]i and its role in pancreatic bicarbonate secretion. Gastroenterology 139:6206312010

  • 102

    Pawar SJSharma RRMahapatra AKLad SDMusa MM: Choroid plexus papilloma of the posterior third ventricle during infancy & childhood: report of two cases with management morbidities. Neurol India 51:3793822003

  • 103

    Peyre MBah AKalamarides M: Multifocal choroid plexus papillomas: case report. Acta Neurochir (Wien) 154:2952992012

  • 104

    Philips MFShanno GDuhaime AC: Treatment of villous hypertrophy of the choroid plexus by endoscopic contact coagulation. Pediatr Neurosurg 28:2522561998

  • 105

    Piechotta KLu JDelpire E: Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). J Biol Chem 277:50812508192002

  • 106

    Pindrik JRocque BGArynchyna AAJohnston JMRozzelle CJ: Radiographic markers of clinical outcomes after endoscopic third ventriculostomy with choroid plexus cauterization: cerebrospinal fluid turbulence and choroid plexus visualization. J Neurosurg Pediatr 18:2872952016

  • 107

    Plotkin MDKaplan MRPeterson LNGullans SRHebert SCDelpire E: Expression of the Na+-K+-2Cl cotransporter BSC2 in the nervous system. Am J Physiol 272:C173C1831997

  • 108

    Poca MASahuquillo J: Short-term medical management of hydrocephalus. Expert Opin Pharmacother 6:152515382005

  • 109

    Pople IKEttles D: The role of endoscopic choroid plexus coagulation in the management of hydrocephalus. Neurosurgery 36:6987021995

  • 110

    Praetorius J: Water and solute secretion by the choroid plexus. Pflugers Arch 454:1182007

  • 111

    Radic JAVincer MMcNeely PD: Outcomes of intraventricular hemorrhage and posthemorrhagic hydrocephalus in a population-based cohort of very preterm infants born to residents of Nova Scotia from 1993 to 2010. J Neurosurg Pediatr 15:5805882015

  • 112

    Raupp P: Acetazolamide in posthaemorrhagic ventricular dilatation. Lancet 352:154815491998

  • 113

    Ray BSPeck FC Jr: Papilloma of the choroid plexus of the lateral ventricles causing hydrocephalus in an infant. J Neurosurg 13:3173221956

  • 114

    Redzic ZBSegal MB: The structure of the choroid plexus and the physiology of the choroid plexus epithelium. Adv Drug Deliv Rev 56:169517162004

  • 115

    Reed DJ: The effect of furosemide on cerebrospinal fluid flow in rabbits. Arch Int Pharmacodyn Ther 178:3243301969

  • 116

    Russell JM: Sodium-potassium-chloride cotransport. Physiol Rev 80:2112762000

  • 117

    Saito ANishimura SFujita TSasaki TNishijima M: A case of difficult management of fluid-electrolyte imbalance in choroid plexus papilloma. Neurol Med Chir (Tokyo) 54:6596632014

  • 118

    Sapiro RKostetskii IOlds-Clarke PGerton GLRadice GLStrauss JF III: Male infertility, impaired sperm motility, and hydrocephalus in mice deficient in sperm-associated antigen 6. Mol Cell Biol 22:629863052002

  • 119

    Scarff JE: The treatment of nonobstructive (communicating) hydrocephalus by endoscopic cauterization of the choroid plexuses. J Neurosurg 33:1181970

  • 120

    Schoeman JDonald Pvan Zyl LKeet MWait J: Tuberculous hydrocephalus: comparison of different treatments with regard to ICP, ventricular size and clinical outcome. Dev Med Child Neurol 33:3964051991

  • 121

    Segal MB: Extracellular and cerebrospinal fluids. J Inherit Metab Dis 16:6176381993

  • 122

    Smith DEJohanson CEKeep RF: Peptide and peptide analog transport systems at the blood-CSF barrier. Adv Drug Deliv Rev 56:176517912004

  • 123

    Smith ZAMoftakhar PMalkasian DXiong ZVinters HVLazareff JA: Choroid plexus hyperplasia: surgical treatment and immunohistochemical results. Case report. J Neurosurg 107:3 Suppl2552622007

  • 124

    Spector RKeep RFRobert Snodgrass SSmith QRJohanson CE: A balanced view of choroid plexus structure and function: Focus on adult humans. Exp Neurol 267:78862015

  • 125

    Stone SSWarf BC: Combined endoscopic third ventriculostomy and choroid plexus cauterization as primary treatment for infant hydrocephalus: a prospective North American series. J Neurosurg Pediatr 14:4394462014

  • 126

    Strahle JGarton HJMaher COMuraszko KMKeep RFXi G: Mechanisms of hydrocephalus after neonatal and adult intraventricular hemorrhage. Transl Stroke Res 3:Suppl 125382012

  • 127

    Tamburrini GCaldarelli MDi Rocco FMassimi LD'Angelo LFasano T: The role of endoscopic choroid plexus coagulation in the surgical management of bilateral choroid plexuses hyperplasia. Childs Nerv Syst 22:6056082006

  • 128

    Tully HMIshak GERue TCDempsey JCBrowd SRMillen KJ: Two hundred thirty-six children with developmental hydrocephalus: causes and clinical consequences. J Child Neurol 31:3093202016

  • 129

    Verkman AS: Mammalian aquaporins: diverse physiological roles and potential clinical significance.. Expert Rev Mol Med 10:e132008

  • 130

    Vogh BPGodman DRMaren TH: Effect of AlCl3 and other acids on cerebrospinal fluid production: a correction. J Pharmacol Exp Ther 243:35391987

  • 131

    Wagshul MEEide PKMadsen JR: The pulsating brain: A review of experimental and clinical studies of intracranial pulsatility.. Fluids Barriers CNS 8:52011

  • 132

    Wagshul MEMcAllister JPRashid SLi JEgnor MRWalker ML: Ventricular dilation and elevated aqueductal pulsations in a new experimental model of communicating hydrocephalus. Exp Neurol 218:33402009

  • 133

    Warf BOndoma SKulkarni ADonnelly RAmpeire MAkona J: Neurocognitive outcome and ventricular volume in children with myelomeningocele treated for hydrocephalus in Uganda. J Neurosurg Pediatr 4:5645702009

  • 134

    Warf BC: Comparison of endoscopic third ventriculostomy alone and combined with choroid plexus cauterization in infants younger than 1 year of age: a prospective study in 550 African children. J Neurosurg 103:6 Suppl4754812005

  • 135

    Warf BC: Congenital idiopathic hydrocephalus of infancy: the results of treatment by endoscopic third ventriculostomy with or without choroid plexus cauterization and suggestions for how it works. Childs Nerv Syst 29:9359402013

  • 136

    Warf BC: Hydrocephalus associated with neural tube defects: characteristics, management, and outcome in sub-Saharan Africa. Childs Nerv Syst 27:158915942011

  • 137

    Warf BC: The impact of combined endoscopic third ventriculostomy and choroid plexus cauterization on the management of pediatric hydrocephalus in developing countries.. World Neurosurg 79:2 SupplS23.e13S23.e152013

  • 138

    Warf BC: Three steps forward and 2 steps back: the Echternach procession toward optimal hydrocephalus treatment. Neurosurgery 61:Suppl 11051102014

  • 139

    Warf BCDewan MMugamba J: Management of Dandy-Walker complex-associated infant hydrocephalus by combined endoscopic third ventriculostomy and choroid plexus cauterization. J Neurosurg Pediatr 8:3773832011

  • 140

    Warf BCMugamba JKulkarni AV: Endoscopic third ventriculostomy in the treatment of childhood hydrocephalus in Uganda: report of a scoring system that predicts success. J Neurosurg Pediatr 5:1431482010

  • 141

    Warf BCTracy SMugamba J: Long-term outcome for endoscopic third ventriculostomy alone or in combination with choroid plexus cauterization for congenital aqueductal stenosis in African infants. J Neurosurg Pediatr 10:1081112012

  • 142

    Warren DTHendson GCochrane DD: Bilateral choroid plexus hyperplasia: a case report and management strategies. Childs Nerv Syst 25:161716222009

  • 143

    Welch KStrand RBresnan MCavazzuti V: Congenital hydrocephalus due to villous hypertrophy of the telencephalic choroid plexuses. Case report. J Neurosurg 59:1721751983

  • 144

    Wellons JC IIITubbs RSLeveque JCBlount JPOakes WJ: Choroid plexectomy reduces neurosurgical intervention in patients with hydranencephaly. Pediatr Neurosurg 36:1481522002

  • 145

    Whitelaw AKennedy CRBrion LP: Diuretic therapy for newborn infants with posthemorrhagic ventricular dilatation.. Cochrane Database Syst Rev 2CD0022702001

  • 146

    Wolburg HPaulus W: Choroid plexus biology and pathology. Acta Neuropathol 119:75882010

  • 147

    Wu QDelpire EHebert SCStrange K: Functional demonstration of Na+-K+-2Cl cotransporter activity in isolated, polarized choroid plexus cells. Am J Physiol 275:C1565C15721998

  • 148

    Yan YDalmasso GNguyen HTObertone TSSitaraman SVMerlin D: Ste20-related proline/alanine-rich kinase (SPAK) regulated transcriptionally by hyperosmolarity is involved in intestinal barrier function.. PLoS One 4:e50492009

  • 149

    Yoshino AKatayama YWatanabe TKurihara JKimura S: Multiple choroid plexus papillomas of the lateral ventricle distinct from villous hypertrophy. Case report. J Neurosurg 88:5815851998

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Kahle, Karimy, Duran, DiLuna, Gerzanich, Simard. Acquisition of data: Kahle, Karimy, Duran, Hu, Gavankar, Gaillard, Rice. Analysis and interpretation of data: Karimy, Duran, Hu, Gavankar, Gaillard, Gerzanich, Simard, Rice. Drafting the article: Kahle, Karimy, Duran, Hu, Gavankar, Gaillard. Critically revising the article: Kahle, Karimy, Duran, Hu, Gerzanich, Simard. Reviewed submitted version of manuscript: Kahle, Karimy, Duran, Bayri, DiLuna, Gerzanich, Simard. Approved the final version of the manuscript on behalf of all authors: Kahle. Administrative/technical/material support: Kahle, DiLuna. Study supervision: Kahle.

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Article Information

INCLUDE WHEN CITING DOI: 10.3171/2016.8.FOCUS16278.

Mr. Karimy and Dr. Duran contributed equally to this work.

Correspondence Kristopher T. Kahle, Department of Neurosurgery, Yale School of Medicine, 300 Cedar St., TAC S311, New Haven, CT 06519. email: kristopher.kahle@yale.edu.

© AANS, except where prohibited by US copyright law.

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    Model for CSF secretion by the CPE; AE2 and NCBE, at an Na/Cl/HCO3 ratio of 18:15:3, transports ions taken up from the basolateral membrane (blood) side into choroid plexus epithelial cells. A large fraction of the Cl and HCO3 influx is recycled across the basolateral membrane. At the luminal (ventricular) side, the Na+/K+-ATPase extrudes most of the Na+. A small contribution to luminal Na+ extrusion is made by NBCe2, which cotransports HCO3. The K-Cl cotransporter, KCC4, a genetic relative of the bumetanide-sensitive Na+-K+-2Cl cotransporter, NKCC1 (see below), which is inhibited by furosemide, secretes the majority of Cl into the CSF lumen. KCC4 is also a main pathway of luminal K+ recycling, which is required for sustained CSF secretion. A fraction of the Na+ extruded into the CSF must reenter the cell via NKCC1 to keep the stoichiometry of the secreted ions to an approximate Na/Cl/HCO3 ratio of 18:15:3. This Na-recycling mechanism is accompanied by extrusion of the imported K+ and Cl via their respective apically expressed ion channels. Because its driving force is close to equilibrium, NKCC1 can mediate the bidirectional transport of ions depending on ion gradients between the blood and CSF. In addition, NKCC1 is highly regulated by SPAK, which in turn is sensitive to changes in intracellular Cl levels and other stimuli, such as osmotic stress and inflammation. It should be noted that ion gradients generated by the primary active Na+/K+-ATPase, which directly pumps out net solute to the CSF, also powers the transcellular movement of ions via the aforementioned Na+- and K+-coupled cotransporters and exchangers. Net ion movement from the blood side to the CSF side creates a small osmolarity difference between these 2 compartments. Water is subsequently “dragged” via osmotic forces across the epithelium and traverses the apical membrane of the choroid plexus epithelial cell through AQP1 in both the luminal and basolateral membranes.

References

1

Abbott NJ: Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 45:5455522004

2

Amin MSReza EWang HLeenen FH: Sodium transport in the choroid plexus and salt-sensitive hypertension. Hypertension 54:8608672009

3

Anei RHayashi YHiroshima SMitsui NOrimoto RUemori G: Hydrocephalus due to diffuse villous hyperplasia of the choroid plexus. Neurol Med Chir (Tokyo) 51:4374412011

4

Aziz AAColeman LMorokoff AMaixner W: Diffuse choroid plexus hyperplasia: an under-diagnosed cause of hydrocephalus in children?. Pediatr Radiol 35:8158182005

5

Ballermann BJStan RV: Resolved: capillary endothelium is a major contributor to the glomerular filtration barrier. J Am Soc Nephrol 18:243224382007

6

Banizs BPike MMMillican CLFerguson WBKomlosi PSheetz J: Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus. Development 132:532953392005

7

Bateman GAAlber MSchuhmann MU: An association between external hydrocephalus in infants and reversible collapse of the venous sinuses. Neuropediatrics 45:1831872014

8

Bateman GABrown KM: The measurement of CSF flow through the aqueduct in normal and hydrocephalic children: from where does it come, to where does it go?. Childs Nerv Syst 28:55632012

9

Begum GYuan HKahle KTLi LWang SShi Y: Inhibition of wnk3 kinase signaling reduces brain damage and accelerates neurological recovery after stroke. Stroke 46:195619652015

10

Bering EA Jr: Circulation of the cerebrospinal fluid. Demonstration of the choroid plexuses as the generator of the force for flow of fluid and ventricular enlargement. J Neurosurg 19:4054131962

11

Bettegowda CAdogwa OMehta VChaichana KLWeingart JCarson BS: Treatment of choroid plexus tumors: a 20-year single institutional experience. J Neurosurg Pediatr 10:3984052012

12

Boivin MJKakooza AMWarf BCDavidson LLGrigorenko EL: Reducing neurodevelopmental disorders and disability through research and interventions. Nature 527:S155S1602015

13

Brinker TStopa EMorrison JKlinge P: A new look at cerebrospinal fluid circulation.. Fluids Barriers CNS 11:102014

14

Britz GWKim DKLoeser JD: Hydrocephalus secondary to diffuse villous hyperplasia of the choroid plexus. Case report and review of the literature. J Neurosurg 85:6896911996

15

Bush A: Primary ciliary dyskinesia. Acta Otorhinolaryngol Belg 54:3173242000

16

Cardia EMolina DAbbate FMastroeni PStassi GGermanà GP: Morphological modifications of the choroid plexus in a rodent model of acute ventriculitis induced by gram-negative liquoral sepsis. Possible implications in the pathophysiology of hypersecretory hydrocephalus. Childs Nerv Syst 11:5115161995

17

Carrion EHertzog JHMedlock MDHauser GJDalton HJ: Use of acetazolamide to decrease cerebrospinal fluid production in chronically ventilated patients with ventriculopleural shunts. Arch Dis Child 84:68712001

18

Casey KFVries JK: Cerebral fluid overproduction in the absence of tumor or villous hypertrophy of the choroid plexus. Childs Nerv Syst 5:3323341989

19

Castañeyra-Ruiz LGonzález-Marrero IGonzález-Toledo JMCastañeyra-Ruiz Ade Paz-Carmona HCastañeyra-Perdomo A: Aquaporin-4 expression in the cerebrospinal fluid in congenital human hydrocephalus.. Fluids Barriers CNS 10:182013

20

Cataltepe OLiptzin DJolley LSmith TW: Diffuse villous hyperplasia of the choroid plexus and its surgical management. J Neurosurg Pediatr 5:5185222010

21

Ceddia ADi Rocco CCarlucci A: [Hypersecretive congenital hydrocephalus due to choroid plexus villous hypertrophy associated with controlateral papilloma.]. Minerva Pediatr 45:3633671993. (Ital)

22

Chen JKnowles HJHebert JLHackett BP: Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry. J Clin Invest 102:107710821998

23

Christensen HLNguyen ATPedersen FDDamkier HH: Na+ dependent acid-base transporters in the choroid plexus insights from slc4 and slc9 gene deletion studies.. Front Physiol 4:3042013

24

Christensen IBGyldenholm TDamkier HHPraetorius J: Polarization of membrane associated proteins in the choroid plexus epithelium from normal and slc4a10 knockout mice.. Front Physiol 4:3442013

25

Cushing H: Studies on the cerebrospinal fluid: I. Introduction. J Med Res 31:1191914

26

Cutler RWPage LGalicich JWatters GV: Formation and absorption of cerebrospinal fluid in man. Brain 91:7077201968

27

D'Ambrosio ALO'Toole JEConnolly ES JrFeldstein NA: Villous hypertrophy versus choroid plexus papilloma: a case report demonstrating a diagnostic role for the proliferation index. Pediatr Neurosurg 39:91962003

28

Damkier HHBrown PDPraetorius J: Cerebrospinal fluid secretion by the choroid plexus. Physiol Rev 93:184718922013

29

Damkier HHBrown PDPraetorius J: Epithelial pathways in choroid plexus electrolyte transport. Physiology (Bethesda) 25:2392492010

30

Dandy WE: Experimental hydrocephalus. Ann Surg 70:1291421919

31

Dandy WE: Extirpation of the choroid plexus of the lateral ventricles in communicating hydrocephalus. Ann Surg 68:5695791918

32

Davy BERobinson ML: Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene. Hum Mol Genet 12:116311702003

33

De Rougemont JAmes A IIINesbett FBHofmann HF: Fluid formed by choroid plexus a technique for its collection and a comparison of its electrolyte composition with serum and cisternal fluids. J Neurophysiol 23:4854951960

34

Del Bigio MR: The ependyma: a protective barrier between brain and cerebrospinal fluid. Glia 14:1131995

35

Di Rocco CIannelli A: Poor outcome of bilateral congenital choroid plexus papillomas with extreme hydrocephalus. Eur Neurol 37:33371997

36

Di Rocco CPettorossi VECaldarelli MMancinelli RVelardi F: Communicating hydrocephalus induced by mechanically increased amplitude of the intraventricular cerebrospinal fluid pressure: experimental studies. Exp Neurol 59:40521978

37

Egnor MZheng LRosiello AGutman FDavis R: A model of pulsations in communicating hydrocephalus. Pediatr Neurosurg 36:2813032002

38

Eisenberg HMMcComb JGLorenzo AV: Cerebrospinal fluid overproduction and hydrocephalus associated with choroid plexus papilloma. J Neurosurg 40:3813851974

39

Erman TGöçer AIErdoğan STuna MIldan FZorludemir S: Choroid plexus papilloma of bilateral lateral ventricle. Acta Neurochir (Wien) 145:1391432003

40

Fairburn B: Choroid plexus papilloma and its relation to hydrocephalus. J Neurosurg 17:1661711960

41

Faivre J: Structure du conarium et des plexus choroide chez l'hommes et des animaux. Gaz Med Paris 9:5555561854

42

Feng XPapadopoulos MCLiu JLi LZhang DZhang H: Sporadic obstructive hydrocephalus in Aqp4 null mice. J Neurosci Res 87:115011552009

43

Filippidis ASKalani MYRekate HL: Hydrocephalus and aquaporins: lessons learned from the bench. Childs Nerv Syst 27:27332011

44

Fisone GSnyder GLFryckstedt JCaplan MJAperia AGreengard P: Na+,K+-ATPase in the choroid plexus Regulation by serotonin/protein kinase C pathway. J Biol Chem 270:242724301995

45

Fujimoto YMatsushita HPlese JPMarino R Jr: Hydrocephalus due to diffuse villous hyperplasia of the choroid plexus. Case report and review of the literature. Pediatr Neurosurg 40:32362004

46

Fujimura MOnuma TKameyama MMotohashi OKon HYamamoto K: Hydrocephalus due to cerebrospinal fluid overproduction by bilateral choroid plexus papillomas. Childs Nerv Syst 20:4854882004

47

Gagnon KBDelpire E: Molecular physiology of SPAK and OSR1: two Ste20-related protein kinases regulating ion transport. Physiol Rev 92:157716172012

48

Gagnon KBEngland RDelpire E: Volume sensitivity of cation-Cl cotransporters is modulated by the interaction of two kinases: Ste20-related proline-alanine-rich kinase and WNK4. Am J Physiol Cell Physiol 290:C134C1422006

49

Garg LCMathur PP: Effect of ouabain on cerebrospinal fluid formation after carbonic anhydrase inhibition. Arch Int Pharmacodyn Ther 213:1901941975

50

Greitz D: Paradigm shift in hydrocephalus research in legacy of Dandy's pioneering work: rationale for third ventriculostomy in communicating hydrocephalus. Childs Nerv Syst 23:4874892007

51

Gudeman SKSullivan HGRosner MJBecker DP: Surgical removal of bilateral papillomas of the choroid plexus of the lateral ventricles with resolution of hydrocephalus. Case report. J Neurosurg 50:6776811979

52

Gupta PSodhi KSMohindra SSaxena AKDas AKhandelwal N: Choroid plexus papilloma of the third ventricle: a rare infantile brain tumor. J Pediatr Neurosci 8:2472492013

53

Hack MCohen AR: Acetazolamide plus furosemide for periventricular dilatation: lessons for drug therapy in children. Lancet 352:4184191998

54

Haliasos NBrew SRobertson FHayward RThompson DChakraborty A: Pre-operative embolisation of choroid plexus tumours in children. Part II. Observations on the effects on CSF production. Childs Nerv Syst 29:71762013

55

Hallaert GGVanhauwaert DJLogghe KVan den Broecke CBaert EVan Roost D: Endoscopic coagulation of choroid plexus hyperplasia. J Neurosurg Pediatr 9:1691772012

56

Hirano HHirahara KAsakura TShimozuru TKadota KKasamo S: Hydrocephalus due to villous hypertrophy of the choroid plexus in the lateral ventricles. Case report. J Neurosurg 80:3213231994

57

Holloway LS JrCassin S: Effect of acetazolamide and ouabain on CSF production rate in the newborn dog. Am J Physiol 223:5035061972

58

Husted RFReed DJ: Regulation of cerebrospinal fluid bicarbonate by the cat choroid plexus. J Physiol 267:4114281977

59

Iencean SM: Simultaneous hypersecretion of CSF and of brain interstitial fluid causes idiopathic intracranial hypertension. Med Hypotheses 61:5295322003

60

Iliff JJChen MJPlog BAZeppenfeld DMSoltero MYang L: Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 34:16180161932014

61

Iliff JJLee HYu MFeng TLogan JNedergaard M: Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 123:129913092013

62

Iliff JJWang MZeppenfeld DMVenkataraman APlog BALiao Y: Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 33:18190181992013

63

International PHVD Drug Trial Group: International randomised controlled trial of acetazolamide and furosemide in posthaemorrhagic ventricular dilatation in infancy. Lancet 352:4334401998

64

Iplikcioglu ACBek SGökduman CABikmaz KCosar M: Diffuse villous hyperplasia of choroid plexus. Acta Neurochir (Wien) 148:6916942006

65

Javaheri SWagner KR: Bumetanide decreases canine cerebrospinal fluid production. In vivo evidence for NaCl cotransport in the central nervous system. J Clin Invest 92:225722611993

66

Jessen NAMunk ASLundgaard INedergaard M: The glymphatic system: a beginner's guide. Neurochem Res 40:258325992015

67

Johanson CMcMillan PTavares RSpangenberger ADuncan JSilverberg G: Homeostatic capabilities of the choroid plexus epithelium in Alzheimer's disease.. Cerebrospinal Fluid Res 1:32004

68

Johanson CEMurphy VADyas M: Ethacrynic acid and furosemide alter Cl, K, and Na distribution between blood, choroid plexus CSF, and brain. Neurochem Res 17:107910851992

69

Johansson PDziegielewska KSaunders N: Low levels of Na, K-ATPase and carbonic anhydrase II during choroid plexus development suggest limited involvement in early CSF secretion. Neurosci Lett 442:77802008

70

Johnson DCSinger SHoop BKazemi H: Chloride flux from blood to CSF: inhibition by furosemide and bumetanide. J Appl Physiol 1985. 63:159116001987

71

Kahle KTKulkarni AVLimbrick DD JrWarf BC: Hydrocephalus in children. Lancet 387:7887992016

72

Kahle KTRing AMLifton RP: Molecular physiology of the WNK kinases. Annu Rev Physiol 70:3293552008

73

Kahle KTSimard JMStaley KJNahed BVJones PSSun D: Molecular mechanisms of ischemic cerebral edema: role of electroneutral ion transport. Physiology (Bethesda) 24:2572652009

74

Karimy JKKahle KTKurland DBYu EGerzanich VSimard JM: A novel method to study cerebrospinal fluid dynamics in rats. J Neurosci Methods 241:78842015

75

Keep RFXiang JBetz AL: Potassium cotransport at the rat choroid plexus. Am J Physiol 267:C1616C16221994

76

Kennedy CRAyers SCampbell MJElbourne DHope PJohnson A: Randomized, controlled trial of acetazolamide and furosemide in posthemorrhagic ventricular dilation in infancy: follow-up at 1 year. Pediatrics 108:5976072001

77

Khanna AWalcott BPKahle KTSimard JM: Effect of glibenclamide on the prevention of secondary brain injury following ischemic stroke in humans. Neurosurg Focus 36:1E112014

78

Kousi MKatsanis N: The genetic basis of hydrocephalus. Annu Rev Neurosci 39:4094352016

79

Krishnamurthy SLi JSchultz LMcAllister JP II: Intraventricular infusion of hyperosmolar dextran induces hydrocephalus: a novel animal model of hydrocephalus.. Cerebrospinal Fluid Res 6:162009

80

Kulkarni AVRiva-Cambrin JBrowd SRDrake JMHolubkov RKestle JR: Endoscopic third ventriculostomy and choroid plexus cauterization in infants with hydrocephalus: a retrospective Hydrocephalus Clinical Research Network study. J Neurosurg Pediatr 14:2242292014

81

Lapras CMertens PGuilburd JNLapras C JrPialat JPatet JD: Choroid plexectomy for the treatment of chronic infected hydrocephalus. Childs Nerv Syst 4:1391431988

82

Lehtinen MKBjornsson CSDymecki SMGilbertson RJHoltzman DMMonuki ES: The choroid plexus and cerebrospinal fluid: emerging roles in development, disease, and therapy. J Neurosci 33:17553175592013

83

Libenson MHKaye EMRosman NPGilmore HE: Acetazolamide and furosemide for posthemorrhagic hydrocephalus of the newborn. Pediatr Neurol 20:1851911999

84

Lindeman GJDagnino LGaubatz SXu YBronson RTWarren HB: A specific, nonproliferative role for E2F-5 in choroid plexus function revealed by gene targeting. Genes Dev 12:109210981998

85

Lorenzo AVHornig GZavala LMBoss VWelch K: Furosemide lowers intracranial pressure by inhibiting CSF production. Z Kinderchir 41:Suppl 110121986

86

Mao XEnno TLDel Bigio MR: Aquaporin 4 changes in rat brain with severe hydrocephalus. Eur J Neurosci 23:292929362006

87

McAllister JP IIWilliams MAWalker MLKestle JRRelkin NRAnderson AM: An update on research priorities in hydrocephalus: overview of the third National Institutes of Health–sponsored symposium “Opportunities for Hydrocephalus Research: Pathways to Better Outcomes”. J Neurosurg 123:142714382015

88

McCarthy KDReed DJ: The effect of acetazolamide and furosemide on cerebrospinal fluid production and choroid plexus carbonic anhydrase activity. J Pharmacol Exp Ther 189:1942011974

89

Milhorat TH: Choroid plexus and cerebrospinal fluid production. Science 166:151415161969

90

Milhorat THHammock MKDavis DAFenstermacher JD: Choroid plexus papilloma. I. Proof of cerebrospinal fluid overproduction. Childs Brain 2:2732891976

91

Milhorat THHammock MKFenstermacher JDLevin VA: Cerebrospinal fluid production by the choroid plexus and brain. Science 173:3303321971

92

Morota NFujiyama Y: Endoscopic coagulation of choroid plexus as treatment for hydrocephalus: indication and surgical technique. Childs Nerv Syst 20:8168202004

93

Murphy VAJohanson CE: Acidosis, acetazolamide, and amiloride: effects on 22Na transfer across the blood-brain and blood-CSF barriers. J Neurochem 52:105810631989

94

Murphy VASmith QRRapoport SI: Homeostasis of brain and cerebrospinal fluid calcium concentrations during chronic hypo- and hypercalcemia. J Neurochem 47:173517411986

95

Nielsen SSmith BLChristensen EIAgre P: Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia. Proc Natl Acad Sci U S A 90:727572791993

96

Nimjee SMPowers CJMcLendon REGrant GAFuchs HE: Single-stage bilateral choroid plexectomy for choroid plexus papilloma in a patient presenting with high cerebrospinal fluid output. J Neurosurg Pediatr 5:3423452010

97

Nógrádi AKelly CCarter ND: Localization of acetazolamide-resistant carbonic anhydrase III in human and rat choroid plexus by immunocytochemistry and in situ hybridisation. Neurosci Lett 151:1621651993

98

Oi SDi Rocco C: Proposal of “evolution theory in cerebrospinal fluid dynamics” and minor pathway hydrocephalus in developing immature brain. Childs Nerv Syst 22:6626692006

99

Oshio KWatanabe HSong YVerkman ASManley GT: Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1. FASEB J 19:76782005

100

Papadopoulos MCVerkman AS: Potential utility of aquaporin modulators for therapy of brain disorders. Prog Brain Res 170:5896012008

101

Park HWNam JHKim JYNamkung WYoon JSLee JS: Dynamic regulation of CFTR bicarbonate permeability by [Cl]i and its role in pancreatic bicarbonate secretion. Gastroenterology 139:6206312010

102

Pawar SJSharma RRMahapatra AKLad SDMusa MM: Choroid plexus papilloma of the posterior third ventricle during infancy & childhood: report of two cases with management morbidities. Neurol India 51:3793822003

103

Peyre MBah AKalamarides M: Multifocal choroid plexus papillomas: case report. Acta Neurochir (Wien) 154:2952992012

104

Philips MFShanno GDuhaime AC: Treatment of villous hypertrophy of the choroid plexus by endoscopic contact coagulation. Pediatr Neurosurg 28:2522561998

105

Piechotta KLu JDelpire E: Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). J Biol Chem 277:50812508192002

106

Pindrik JRocque BGArynchyna AAJohnston JMRozzelle CJ: Radiographic markers of clinical outcomes after endoscopic third ventriculostomy with choroid plexus cauterization: cerebrospinal fluid turbulence and choroid plexus visualization. J Neurosurg Pediatr 18:2872952016

107

Plotkin MDKaplan MRPeterson LNGullans SRHebert SCDelpire E: Expression of the Na+-K+-2Cl cotransporter BSC2 in the nervous system. Am J Physiol 272:C173C1831997

108

Poca MASahuquillo J: Short-term medical management of hydrocephalus. Expert Opin Pharmacother 6:152515382005

109

Pople IKEttles D: The role of endoscopic choroid plexus coagulation in the management of hydrocephalus. Neurosurgery 36:6987021995

110

Praetorius J: Water and solute secretion by the choroid plexus. Pflugers Arch 454:1182007

111

Radic JAVincer MMcNeely PD: Outcomes of intraventricular hemorrhage and posthemorrhagic hydrocephalus in a population-based cohort of very preterm infants born to residents of Nova Scotia from 1993 to 2010. J Neurosurg Pediatr 15:5805882015

112

Raupp P: Acetazolamide in posthaemorrhagic ventricular dilatation. Lancet 352:154815491998

113

Ray BSPeck FC Jr: Papilloma of the choroid plexus of the lateral ventricles causing hydrocephalus in an infant. J Neurosurg 13:3173221956

114

Redzic ZBSegal MB: The structure of the choroid plexus and the physiology of the choroid plexus epithelium. Adv Drug Deliv Rev 56:169517162004

115

Reed DJ: The effect of furosemide on cerebrospinal fluid flow in rabbits. Arch Int Pharmacodyn Ther 178:3243301969

116

Russell JM: Sodium-potassium-chloride cotransport. Physiol Rev 80:2112762000

117

Saito ANishimura SFujita TSasaki TNishijima M: A case of difficult management of fluid-electrolyte imbalance in choroid plexus papilloma. Neurol Med Chir (Tokyo) 54:6596632014

118

Sapiro RKostetskii IOlds-Clarke PGerton GLRadice GLStrauss JF III: Male infertility, impaired sperm motility, and hydrocephalus in mice deficient in sperm-associated antigen 6. Mol Cell Biol 22:629863052002

119

Scarff JE: The treatment of nonobstructive (communicating) hydrocephalus by endoscopic cauterization of the choroid plexuses. J Neurosurg 33:1181970

120

Schoeman JDonald Pvan Zyl LKeet MWait J: Tuberculous hydrocephalus: comparison of different treatments with regard to ICP, ventricular size and clinical outcome. Dev Med Child Neurol 33:3964051991

121

Segal MB: Extracellular and cerebrospinal fluids. J Inherit Metab Dis 16:6176381993

122

Smith DEJohanson CEKeep RF: Peptide and peptide analog transport systems at the blood-CSF barrier. Adv Drug Deliv Rev 56:176517912004

123

Smith ZAMoftakhar PMalkasian DXiong ZVinters HVLazareff JA: Choroid plexus hyperplasia: surgical treatment and immunohistochemical results. Case report. J Neurosurg 107:3 Suppl2552622007

124

Spector RKeep RFRobert Snodgrass SSmith QRJohanson CE: A balanced view of choroid plexus structure and function: Focus on adult humans. Exp Neurol 267:78862015

125

Stone SSWarf BC: Combined endoscopic third ventriculostomy and choroid plexus cauterization as primary treatment for infant hydrocephalus: a prospective North American series. J Neurosurg Pediatr 14:4394462014

126

Strahle JGarton HJMaher COMuraszko KMKeep RFXi G: Mechanisms of hydrocephalus after neonatal and adult intraventricular hemorrhage. Transl Stroke Res 3:Suppl 125382012

127

Tamburrini GCaldarelli MDi Rocco FMassimi LD'Angelo LFasano T: The role of endoscopic choroid plexus coagulation in the surgical management of bilateral choroid plexuses hyperplasia. Childs Nerv Syst 22:6056082006

128

Tully HMIshak GERue TCDempsey JCBrowd SRMillen KJ: Two hundred thirty-six children with developmental hydrocephalus: causes and clinical consequences. J Child Neurol 31:3093202016

129

Verkman AS: Mammalian aquaporins: diverse physiological roles and potential clinical significance.. Expert Rev Mol Med 10:e132008

130

Vogh BPGodman DRMaren TH: Effect of AlCl3 and other acids on cerebrospinal fluid production: a correction. J Pharmacol Exp Ther 243:35391987

131

Wagshul MEEide PKMadsen JR: The pulsating brain: A review of experimental and clinical studies of intracranial pulsatility.. Fluids Barriers CNS 8:52011

132

Wagshul MEMcAllister JPRashid SLi JEgnor MRWalker ML: Ventricular dilation and elevated aqueductal pulsations in a new experimental model of communicating hydrocephalus. Exp Neurol 218:33402009

133

Warf BOndoma SKulkarni ADonnelly RAmpeire MAkona J: Neurocognitive outcome and ventricular volume in children with myelomeningocele treated for hydrocephalus in Uganda. J Neurosurg Pediatr 4:5645702009

134

Warf BC: Comparison of endoscopic third ventriculostomy alone and combined with choroid plexus cauterization in infants younger than 1 year of age: a prospective study in 550 African children. J Neurosurg 103:6 Suppl4754812005

135

Warf BC: Congenital idiopathic hydrocephalus of infancy: the results of treatment by endoscopic third ventriculostomy with or without choroid plexus cauterization and suggestions for how it works. Childs Nerv Syst 29:9359402013

136

Warf BC: Hydrocephalus associated with neural tube defects: characteristics, management, and outcome in sub-Saharan Africa. Childs Nerv Syst 27:158915942011

137

Warf BC: The impact of combined endoscopic third ventriculostomy and choroid plexus cauterization on the management of pediatric hydrocephalus in developing countries.. World Neurosurg 79:2 SupplS23.e13S23.e152013

138

Warf BC: Three steps forward and 2 steps back: the Echternach procession toward optimal hydrocephalus treatment. Neurosurgery 61:Suppl 11051102014

139

Warf BCDewan MMugamba J: Management of Dandy-Walker complex-associated infant hydrocephalus by combined endoscopic third ventriculostomy and choroid plexus cauterization. J Neurosurg Pediatr 8:3773832011

140

Warf BCMugamba JKulkarni AV: Endoscopic third ventriculostomy in the treatment of childhood hydrocephalus in Uganda: report of a scoring system that predicts success. J Neurosurg Pediatr 5:1431482010

141

Warf BCTracy SMugamba J: Long-term outcome for endoscopic third ventriculostomy alone or in combination with choroid plexus cauterization for congenital aqueductal stenosis in African infants. J Neurosurg Pediatr 10:1081112012

142

Warren DTHendson GCochrane DD: Bilateral choroid plexus hyperplasia: a case report and management strategies. Childs Nerv Syst 25:161716222009

143

Welch KStrand RBresnan MCavazzuti V: Congenital hydrocephalus due to villous hypertrophy of the telencephalic choroid plexuses. Case report. J Neurosurg 59:1721751983

144

Wellons JC IIITubbs RSLeveque JCBlount JPOakes WJ: Choroid plexectomy reduces neurosurgical intervention in patients with hydranencephaly. Pediatr Neurosurg 36:1481522002

145

Whitelaw AKennedy CRBrion LP: Diuretic therapy for newborn infants with posthemorrhagic ventricular dilatation.. Cochrane Database Syst Rev 2CD0022702001

146

Wolburg HPaulus W: Choroid plexus biology and pathology. Acta Neuropathol 119:75882010

147

Wu QDelpire EHebert SCStrange K: Functional demonstration of Na+-K+-2Cl cotransporter activity in isolated, polarized choroid plexus cells. Am J Physiol 275:C1565C15721998

148

Yan YDalmasso GNguyen HTObertone TSSitaraman SVMerlin D: Ste20-related proline/alanine-rich kinase (SPAK) regulated transcriptionally by hyperosmolarity is involved in intestinal barrier function.. PLoS One 4:e50492009

149

Yoshino AKatayama YWatanabe TKurihara JKimura S: Multiple choroid plexus papillomas of the lateral ventricle distinct from villous hypertrophy. Case report. J Neurosurg 88:5815851998

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