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
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.
Case reports of hydrocephalus associated with CSF hypersecretion
| Pathology | Age & Sex | CSF Secretion (ml/24 hrs) | Method of Measurement | Authors & Year |
|---|---|---|---|---|
| CPP | 10 days, F | 800–1000 | EVD | Di Rocco & Iannelli, 1997 |
| 5 mos, F | 2000* | VLP | Eisenberg et al., 1974 | |
| 15 mos, F | 400–960 | EVD | Fairburn, 1960 | |
| 10 mos, M | 2000 | EVD | Fujimura et al., 2004 | |
| 3.5 yrs, F | 2280* | EVD | Gudeman et al., 1979 | |
| 23 mos, M | 1500* | VLP | Milhorat et al., 1976 | |
| 6 mos, F | 3200–5000 | EVD | Nimjee et al., 2010 | |
| 8 mos, F | 1400–1500 | EVD | Pawar et al., 2003 | |
| 2 yrs, M | 900–1200 | EVD | Pawar et al., 2003 | |
| 22 mos, F | 800–1500 | EVD | Saito et al., 2014 | |
| CPH | 8 mos, F | 1500 | EVD | Anei et al., 2011 |
| 11 yrs, M | 4200* | EVD | Aziz et al., 2005 | |
| 3 mos, M | 900 | EVD | Britz et al., 1996 | |
| 9 days, M | 2000 | EVD | Cataltepe et al., 2010 | |
| 7 mos, F | 1200 | EVD | D'Ambrosio et al., 2003 | |
| 3 yrs, F | 2000 | EVD | Hallaert et al., 2012 | |
| 7 yrs, F | 2000 | EVD | Hirano et al., 1994 | |
| 15 mos, F | 1400 | EVD | Smith et al., 2007 | |
| 24 mos, F | 2000 | EVD | Tamburrini et al., 2006 | |
| Unknown | 2.5 yrs, NA | 2000* | EVD | Casey & 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.
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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.
