Journal of Clinical Medicine Review How to Choose a Shunt for Patients with Normal Pressure Hydrocephalus: A Short Guide to Selecting the Best Shunt Assembly Juan Sahuquillo 1,2,3, * , Katiuska Rosas 1,2 , Helena Calvo 1 , Aloma Alcina 1 , Dario Gándara 1,2 , Diego López-Bermeo 1 and Maria-Antonia Poca 1,2,3 1 Department of Neurosurgery, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain; krosas@vhebron.net (K.R.); hcalvo_rubio@vhebron.net (H.C.); aalcina@vhebron.net (A.A.); dfgandar@vhebron.net (D.G.); diego.lopez@vhebron.net (D.L.-B.); pocama@neurotrauma.net (M.-A.P.) 2 Neurotrauma and Neurosurgery Research Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain 3 Department of Surgery, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain * Correspondence: sahuquillo@neurotrauma.net Abstract: Most patients with hydrocephalus are still managed with the implantation of a cere- brospinal fluid (CSF) shunt in which the CSF flow is regulated by a differential-pressure valve (DPV). Our aim in this review is to discuss some basic concepts in fluid mechanics that are frequently ignored   but that should be understood by neurosurgeons to enable them to choose the most adequate shunt for each patient. We will present data, some of which is not provided by manufacturers, which may Citation: Sahuquillo, J.; Rosas, K.; help neurosurgeons in selecting the most appropriate shunt. To do so, we focused on the management Calvo, H.; Alcina, A.; Gándara, D.; of patients with idiopathic “normal-pressure hydrocephalus” (iNPH), as one of the most challenging López-Bermeo, D.; Poca, M.-A. How to Choose a Shunt for Patients with scenarios, in which the combination of optimal technology, patient characteristics, and knowledge Normal Pressure Hydrocephalus: A of fluid mechanics can significantly modify the surgical results. For a better understanding of the Short Guide to Selecting the Best available hardware and its evolution over time, we will have a second look at the design of the first Shunt Assembly. J. Clin. Med. 2021, DPV and the reasons why additional devices were incorporated to control for shunt overdrainage 10, 1210. https://doi.org/10.3390/ and its related complications. We try to persuade the reader that a clear understanding of the physical jcm10061210 concepts of the CSF and shunt dynamics is key to understand the pathophysiology of iNPH and to improve its treatment. Academic Editor: Giuseppe Lanza Keywords: differential-pressure valves; hydrocephalus; normal-pressure hydrocephalus; fluid me- Received: 6 February 2021 chanics; shunt overdrainage; antisiphon device Accepted: 8 March 2021 Published: 15 March 2021 Publisher’s Note: MDPI stays neutral 1. Background with regard to jurisdictional claims in published maps and institutional affil- Hydrocephalus is the most frequent cause of acute and chronic intracranial hyper- iations. tension both in children and adults and is the condition that pediatric neurosurgeons treat most frequently. Despite the popularity of endoscopic third ventriculostomy in the neurosurgical armamentarium, most patients with hydrocephalus are still managed with the implantation of a cerebrospinal fluid (CSF) shunt in which the CSF flow is regulated by Copyright: © 2021 by the authors. a differential-pressure valve (DPV). The first generation DPVs were introduced in the 1950s Licensee MDPI, Basel, Switzerland. and most of the valves designed soon after World War II are still used today, with minor This article is an open access article modifications [1,2]. In the last two decades, shunt technology has evolved significantly distributed under the terms and and in addition to the conventional DPVs, today we have at our disposal “programmable” conditions of the Creative Commons valves, flow-regulated valves, antisiphon and gravitational devices, and many shunt assem- Attribution (CC BY) license (https:// blies with significantly different hydrodynamic profiles. In a review conducted by Aschoff creativecommons.org/licenses/by/ in 2017, about 160 different shunt designs were available on the market [1] distributed by 4.0/). twelve manufacturers worldwide [3]. J. Clin. Med. 2021, 10, 1210. https://doi.org/10.3390/jcm10061210 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 1210 2 of 18 Until recent years, the most complex problem neurosurgeons faced was to choose among a low-, medium- or high-pressure DPV [3]. The wide range of designs and functional complexity of shunt assemblies currently available allow reduction of the complications of shunt over- or under-drainage and to improve the long-term outcome of patients with hydrocephalus. However, the information provided by manufacturers regarding the dif- ferent types of valves is scarce and somewhat misleading, and basic fluid mechanics is not part of the standard training of neurosurgeons. In acute posthemorrhagic or tumoral hydrocephalus, any simple DPV available on the market will work but, in complex clinical scenarios, such as in patients with pseudotumor cerebri, arachnoid cysts, negative-pressure hydrocephalus, slit-ventricle syndrome, hydrocephalus in the pediatric population, and in patients with idiopathic “normal-pressure hydrocephalus” (iNPH) syndrome, the appro- priate selection of shunt hardware is crucial for obtaining the best possible outcome and reducing shunt-associated complications. Current shunt technology allows for selection among a wide variety of hardware and adapts it to patients’ age, height, weight, clinical, and neuroradiological characteristics. This selection is especially relevant in patients with iNPH in which the shunt selection is essential to reduce both the rate of nonresponders and shunt-related complications. In pediatric neurosurgery, the goal of selecting the most adequate shunt hardware is to reduce the number of shunt-failures that infants and children will have until they become adults, an important factor in obtaining their best long-term outcomes and social integration. Our aim in this review is to discuss some basic concepts in fluid mechanics that are frequently ignored but that should be understood by neurosurgeons to enable them to choose the most adequate shunt for each patient. We present data, some of which is not provided by manufacturers, which may help neurosurgeons in selecting the most appropriate shunt. To do so, we focus on the management of patients with iNPH, as one of the most challenging scenarios, in which the combination of optimal technology, patient characteristics, and knowledge of fluid mechanics can significantly modify the surgical results. Although our statement seems to be contradictory with the lack of evidence that any valve or shunt assembly is superior in managing hydrocephalus [4], we hope to persuade the reader of the need to reconsider the old concepts regarding DPV. 2. How Neurosurgeons Select a Shunt? In brief, a modern CSF shunt has five major components: (1) a ventricular catheter, (2) a reservoir, (3) a valve system, (4) an antisiphon (ASD)/gravity compensating-device, and (4) a distal catheter [5,6]. Because the designs of the proximal and distal catheters are quite constant among manufacturers (with internal diameters (ID) that are usually greater than 0.80 mm) their relevance is of minor interest. However, the valve design and the incorporation of an ASD/gravity-compensating accessory, whether integrated in the valve or inserted in series, significantly modifies the hydrodynamic performance of a shunt. In an excellent but undercited paper about shunts, Turner stated that “neurosurgeons approach the choice of hardware for use in a ventriculoperitoneal shunt in much the same way they buy a car” [5]. In his own words, neurosurgeons use “ . . . style, past experience, brand loyalty, advertising, comfort, training, and a little science to choose a combination of hardware and surgical procedure” [5]. This caustic remark reflects the reality of shunt surgery in many neurosurgical departments in which the hydrodynamic knowledge of residents and staff is suboptimal most of the time, and shunt surgery is considered a nonglamorous and technically simple surgical procedure that is frequently assigned to residents or junior staff. Frequently, the selection of hardware for implantation is based on the stock each neurosurgical department owns that is still generally based in the simple and misleading concept of low-, medium- and high-pressure DPVs. For a better understanding of the available hardware and its evolution over time, we will have a second look at the design of the first DPV and the reasons why additional devices were incorporated to control for shunt overdrainage and its related complications [7]. We try to persuade the reader that a clear understanding of the physical concepts of the CSF J. Clin. Med. 2021, 10, x FOR PEER REVIEW 3 of 19 For a better understanding of the available hardware and its evolution over time, we J. Clin. Med. 2021, 10, 1210 will have a second look at the design of the first DPV and the reasons why additional3 of 18 devices were incorporated to control for shunt overdrainage and its related complica- tions [7]. We try to persuade the reader that a clear understanding of the physical con- cepts of the CSF and shunt dynamics is key to understand the pathophysiology of NPH and shunt dynamics is key to understand the pathophysiology of NPH and to improve and to improve its treatment. its treatment. 3. 3. Differential-Pressure Differential-Pressure Valves: Valves: The First Generation The First Generation One One ofof the first attempts the first attempts in in managing managing hydrocephalus hydrocephalus was was reported reported by by Dandy Dandy who who proposed third ventriculostomy to treat obstructive hydrocephalus proposed third ventriculostomy to treat obstructive hydrocephalus and the extirpation/ and the extirpa- tion/coagulation coagulation of theofchoroidthe choroid plexusplexus in communicating in communicating hydrocephalus hydrocephalus [8]. Early [8]. Early at- attempts to tempts to divert the CSF from the cerebral ventricles with saphenous divert the CSF from the cerebral ventricles with saphenous grafts to the sagittal sinus grafts to the sagittal or sinus to the or to the heart heart atrium atrium with simple withtubessimple madetubes maderubber, of plastic, of plastic, rubber, or metal wereorunsuccessful metal were unsuccessful because they because they become become clogged by bloodclogged when bytheblood when venous the venous pressure pressure was was increased by anyin- creased Valsalvaby any Valsalva maneuver [8]. maneuver [8]. The discovery discovery of ofthe thesilicone siliconeelastomers elastomers inin 1943 1943 was was a significant a significant milestone milestone in med- in medicine. icine. Silicone is an inert material with low interaction with biological Silicone is an inert material with low interaction with biological tissues that sustains high tissues that sus- tains high temperatures temperatures and therefore,and therefore, it can be sterilized it can be sterilized [9]. The [9]. The first first documented documented attempt at- to tempt use antointernal use an internal shunt withshunt a with a unidirectional unidirectional valve valve to avoidto avoid refluxreflux was was reported reported by by the the neurosurgeons neurosurgeons NulsenNulsen and Spitz and Spitz in 1952inin1952 in cooperation cooperation with scientists with scientists from Dow from Dow Corning, a USA company Corning, specialized a USA company in silicon-derived specialized polymerspolymers in silicon-derived [9,10]. Later, [9,10].Spitz implanted Later, Spitz im- a unidirectional planted valve designed a unidirectional valve by Holter for designed by his ownfor Holter sonhis asown documented in a captivating son as documented in a history by Baru captivating et al. history by[11]. BaruInetthe al.patent [11]. Infiled the in 1956 filed patent by Holter in 1956andbyNulsen, Holter the andreported Nulsen, purpose the of the reported unidirectional purpose valve was “the of the unidirectional valveprevention of reverse flow was “the prevention and providing of reverse flow and for a pumping providing for a operation pumping for insuring operation forthat the device insuring is functioning that the properly”properly” device is functioning [12]. The first valve [12]. model The first consisted valve modelof two in-series consisted of two silicon tubessilicon in-series with lateral tubes slits withencased lateral within slits en-a sleevewithin cased (Figurea 1). The(Figure sleeve slits in the silicone 1). The slits acted in the as a DPVacted silicone by allowing as a DPV flow by through allowingthem flow when differential through them when pressure was ≥30 differential mmH2 O pressure (2.2≥30 was mmHg) mmH[12]. ThemmHg) 2O (2.2 first DPV valves [12]. Thewere first DPV valves were introduced in the early 1950s by a reduced group of neurosurgeons[2] introduced in the early 1950s by a reduced group of neurosurgeons in the United States in andUnited the the designs Statesmade by Pudenz [2] and the designs and made Holterby were the first Pudenz anddesigns Holter used werefor thethe treatment first designs of hydrocephalus used for the treatment[2,8].of hydrocephalus [2,8]. Figure 1. Figure 1. (Left). (Left). Reproduced Reproducedwith withpermission permissionfrom fromA.A.Aschoff. Three Aschoff. different Three Holter different valve Holter designs valve are are designs shown. The first shown. The valve on top is the oldest model (circa 1970), more recent designs in the middle and on the bottom. This valve first valve on top is the oldest model (circa 1970), more recent designs in the middle and on the bottom. This valve was was dis- continued and no longer available. (Right). Reproduced from Figures 2 and 3 of the patent filed 2 October 1956 by Holter discontinued and no longer available. (Right). Reproduced from Figures 2 and 3 of the patent filed 2 October 1956 by Holter and Spitz [12]. Both figures are enlarged sections showing the inlet (FIG. 2) and outlet valves (FIG. 3) of the device. Labels and Spitz [12]. Both figures are enlarged sections showing the inlet (FIG. 2) and outlet valves (FIG. 3) of the device. Labels 22 and 38 show the inlet and outlet tubes with lateral slits “three-sixteenth inch in length” (0.80 cm), which functions as 22 theand 38 show actual valve.the inlet and outlet tubes with lateral slits “three-sixteenth inch in length” (0.80 cm), which functions as the actual valve. As shown in Figure 2, IVP and the HP within the shunt contribute to P1, while the sum of the CP of the DPV valve and the intracavitary pressure where the distal catheter is placed contribute to P2. For the sake of simplicity, we consider that the cavity in which CSF is shunted is the peritoneal cavity and therefore the intraperitoneal pressure (IPP) is J. Clin. Med. 2021, 10, 1210 the outlet pressure. An important concept to grasp is that in any DPV, the valve will4 of be 18 always closed when PPshunt is ≤0, and it will open when PPshunt is >0. Once the valve is opened, the CSF flow through the shunt will be regulated by Equation (2). Figure 2.2. (Top). Figure (Top). In In this this figure, figure, the the pressures pressures defining definingthe theperfusion perfusionpressure pressureofofthe thevalve valve(PP(PP ) are ) are valve valve shown. shown. P1the P1 is is the pressure pressure at the at the inletinlet of valve of the the valve and and P2 atPthe 2 atoutlet. the outlet. P1 sum P1 is the is theofsum of the intraventricular the intraventricular pressure pressure (IVP) and(IVP) the and the gravita- tional-induced hydrostatic gravitational-induced pressure hydrostatic (HP).(HP). pressure P2 isPthe 2 is sum of the the sum closing of the pressure closing pressure(CP) (CP)ofofthe thevalve valveand and the intraperitonal intraperitonal pressure(IPP) pressure (IPP)ififthe thedistal distalcatheter catheterisisplaced placedin inthe theperitoneum peritoneumor orthe theintra-atrial intra-atrial pressure pressure (IAP) (IAP) ififthe thedistal distaltip tipisisplaced placed within the right atrium. (Bottom). When the shunted patient is recumbent, the hydrostatic difference within the right atrium. (Bottom). When the shunted patient is recumbent, the hydrostatic difference between the tips between the tipsofof J. Clin. the Med.ventricular 2021, 10, x FOR andPEER REVIEW catheters is negligible and ~0 mmHg; therefore, the HP in the equation that calculates intraperitoneal 6 of 19 the ventricular and intraperitoneal catheters is negligible and ~0 mmHg; therefore, the HP in the equation that calculates the PPvalve can be removed. the PPvalve can be removed. The definitions provided for opening pressure (OP) and CP in a DPV in many pub- lished papers are misleading. Most manufacturers report either the OP or the CP as re- quired by the International Organization for Standardization (ISO), ISO 7197:2006, which regulates the minimum mechanical and technical requirements that manufacturers should report for implants used in the treatment of hydrocephalus [19]. OP is obtained from flow–pressure tests conducted in standardized testing rigs and is defined as the differential pressure above which flow of deaerated and deionized water through the valve starts at a fixed rate of 20 mL/h [19,20]. CP is the differential pressure below which the flow through the shunt ceases once the infusion pump in the testing rig stops [21]. In most valves, OP and CP are similar; therefore, the differences are clinically irrelevant. ISO 7197:2006 dictates that shunt manufacturers report the flow–pressure tests at 20 mL/h for their valves; they are classified as extra-low, low, medium, or high-pressure according to the pressure generated as this fixed flow rate. However, manufacturers usually report the flow–pressure data on a continuous scale from 5 to 50 mL/h (Figure 4). Figure 3. This This figure shows thethe changes changes ininPP PPvalve valve when when aa shunted shunted patient is standing. In this scenario, scenario, the the IVP IVP is is ≤ ≤00 mmHg mmHg and the gravitational-induced and the gravitational-induced HP HPisisequal equaltotothe theheight heightbetween betweenthethe tips tips of of thethe ventricular ventricular and and distal distal catheters. catheters. In aIn173 a 173 cm cm height height adult, adult, thisthis difference difference cancan be be equal equal to to 7070 cm, cm, which which willgenerate will generatea agravitational gravitationalHP HPofof51.2 51.2mmHg. mmHg. If If the the patient patient has has an an implanted implanted differential-pressure valve (DPV) differential-pressure valve (DPV) with with anan opening opening pressure pressure (OP) (OP) of of 55 cmH cmH2O O (3.7 mmHg) without any 2 (3.7 mmHg) without any gravitational or antisiphon device, and assuming an IPP of 0–3 mmHg, these conditions will generate a PPvalve in a gravitational or antisiphon device, and assuming an IPP of 0–3 mmHg, these conditions will generate a PP in a standing standing patient of ~44 mmHg and therefore the valve will be permanently open when patient is sitting valve or standing. patient of ~44 mmHg and therefore the valve will be permanently open when patient is sitting or standing. J. Clin. Med. 2021, 10, 1210 5 of 18 4. Basic Fluid Mechanics Required to Understand Shunts and Valves In any nonelastic tube, liquid flow is driven by the pressure difference between the inlet and outlet. This was the remarkable finding that Poiseuille found in the experiments he designed to understand the laws governing blood flow in the microcirculation [13]. Poiseuille’s law describes the relationship between flow (Q) and pressure of any Newtonian liquid circulating through rigid tubes with nonturbulent (laminar) flow [14]. This equation is frequently used in physiology, engineering, and biology: (P1 − P2 )πR4 Q= , (1) 8ηι In Equation (1), P1 and P2 are the pressures at the inlet and the outlet of the tube, respectively, R is the radius of the tube, η the viscosity of the fluid, L the length of the tube, and π and 8 are constants. The viscosity of CSF is close to the viscosity of water, which is 0.7–1 mPa-s at a temperature of 37 ◦ C [15]. Q in a rigid tube is directly proportional to P1 –P2 and inversely proportional to the resistance of the tube that depends on R, η, and L. However, in any shunt assembly, the distal tube is only a part of a more complex design and therefore the total resistance of the shunt (Rshunt ) is always higher than the resistance of the distal catheter. To address this issue, the analogy between steady-state electrical current flow in an electric circuit and the flow of an incompressible fluid in a nonelastic tube is helpful. In an electric circuit, the electric flow is defined by Ohm’s law that when applied to fluid dynamics can be restated: (P − P2 ) Q= 1 , (2) Rshunt in which (P1 –P2 ) is the inlet–outlet differential pressure and Rshunt the total resistance of the shunt assembly. In an electrical circuit in which resistors are connected in series, the total resistance (impedance) will be calculated by adding up the impedance of the individual resistors: R = R1 + R2 + R3 + . . . . If an electric circuit has three in series resistors with an impedance of 8 Ω, 3 Ω, and 2 Ω respectively, the total impedance of the circuit will be 13 Ω. In a similar way, the total resistance of a shunt (Rshunt ) is calculated by adding the resistance of all the individual components in the shunt assembly: Rshunt = Rvent + Rdist + Rvalue + Rgrav , (3) In Equation (3), Rshunt is obtained by adding the individual resistances of the ven- tricular catheter (Rvent ), the distal catheter (Rdist ), the resistance of the valve (Rvalve ), and that of any additional device added in series to compensate for gravitational changes (Rgrav ). The normal resistance to CSF outflow (Rout ) in healthy individuals ranges from 5 to 10 mmHg/mL/min, and this resistance increases with age [16,17]. When a patient with hydrocephalus undergoes a shunt implantation, both the shunt and the residual absorption capacity of the patient do work in parallel, and therefore, to reproduce the normal physiology the total resistance of both working together should be close to these physiological values. 5. Which Pressures Govern Cerebrospinal Fluid Flow in an Implanted Shunt Assembly? In vitro, the flow across a shunt assembly, as defined in Equation (1), is directly proportional to the driving pressure, which is the difference between the inlet (P1 ) and outlet pressures (P2 ) and inversely proportional to the total resistance of the shunt (Rshunt ) as defined in Equations (2) and (3). For a better understanding of the CSF dynamics across a shunt, it is useful to use the concept of “shunt perfusion pressure” (PPshunt ) introduced by Rayport and Reiss [14], a term familiar to any medical student learning the regulation of blood flow through the capillary beds of any organ. Rayport and Reiss defined PPshunt in VA shunts as the algebraic J. Clin. Med. 2021, 10, x FOR PEER REVIEW 6 of 19 J. Clin. Med. 2021, 10, 1210 6 of 18 difference between the intraventricular pressure (IVP) and either the closing pressure (CP) of the DPV valve or the atrial pressure, “whichever is larger” [14]. In 1972, Fox et al. modified the PPshunt concept by introducing the gravitational-induced hydrostatic pressure (HP) in the algebraic definition (Figure 2) [18]. HP is the gravitational-induced pressure generated by the column of CSF fluid in the shunt when the patient is standing or sitting and equals the difference in height between the tip of the ventricular catheter and the distal tip of the shunt. This HP is negligible when the patient is recumbent but can increase to 50 to 70 cmH2 O (~37–50 mmHg) when a medium-height shunted patient is sitting or standing (Figure 3). As shown in Figure 2, IVP and the HP within the shunt contribute to P1 , while the sum of the CP of the DPV valve and the intracavitary pressure where the distal catheter is placed contribute to P2 . For the sake of simplicity, we consider that the cavity in which CSF is shunted is the peritoneal cavity and therefore the intraperitoneal pressure (IPP) is the outlet pressure. An important concept to grasp is that in any DPV, the valve will be always closed when PPshunt is ≤0, and it will open when PPshunt is >0. Once the valve is opened, the CSF flow through the shunt will be regulated by Equation (2). The definitions provided for opening pressure (OP) and CP in a DPV in many pub- lished papers are misleading. Most manufacturers report either the OP or the CP as required by the International Organization for Standardization (ISO), ISO 7197:2006, which regulates the minimum mechanical and technical requirements that manufacturers should report for implants used in the treatment of hydrocephalus [19]. OP is obtained from flow–pressure tests conducted in standardized testing rigs and is defined as the differential pressure above which flow of deaerated and deionized water through the valve starts at a fixed rate of 20 mL/h [19,20]. CP is the differential pressure below which the flow through the shunt ceases once the infusion pump in the testing rig stops [21]. In most valves, OP and Figure 3. This figure shows the changes in PPvalve when a shunted patient is standing. In this scenario, the IVP is ≤0 mmHg CP are similar; therefore, the differences are clinically irrelevant. ISO 7197:2006 dictates that and the gravitational-induced HP is equal to the height between the tips of the ventricular and distal catheters. In a 173 shunt manufacturers report the flow–pressure tests at 20 mL/h for their valves; they are cm height adult, this difference can be equal to 70 cm, which will generate a gravitational HP of 51.2 mmHg. If the patient classified asvalve has an implanted differential-pressure extra-low, (DPV) low, with medium, an openingorpressure high-pressure (OP) of according 5 cmH2O (3.7to mmHg) the pressure generated without any gravitational or antisiphon device, and assuming an IPP of 0–3 mmHg, these conditions will generate a PPvalvedata as this fixed flow rate. However, manufacturers usually report the flow–pressure in aon a standing patient of ~44 mmHgcontinuous scalethe and therefore from 5 towill valve 50 be mL/h (Figure open permanently 4). when patient is sitting or standing. Figure 4.4.Figure Figure Figurereproduced reproduced with permission with permissionfrom the Natus from Neurosurgery the Natus and Neurocritical Neurosurgery Care- and Neurocritical CareProduct Product and Accessory and Accessory Catalog,Catalog, 2019 (https://natus.com, 2019 (https://natus.com, accessed accessed on 232020). on 23 June June In 2020). In this this graph, graph, the the flow–pressure flow–pressure dataContour-Flex™ data for the for the Contour-Flex™ familyare family of valves of valves shown.are shown. Contour-Flex™ Contour-Flex™ are typical silicone diaphragm valves with a low–medium- and high-pressure ranges. Flow rates in therates are typical silicone diaphragm valves with a low–medium- and high-pressure ranges. Flow in x-axis represent a variable flow rate from 1 to 50 mL/h while in the y-axis the pressure generated at each flow rate is shown. Colored bands define the variability of the pressures obtained for each flow rate. the x-axis represent a variable flow rate from 1 to 50 mL/h while in the y-axis the pressure gener- ated at each flow rate is shown. Colored bands define the variability of the pressures obtained for J. Clin. Med. 2021, 10, 1210 each flow rate. 7 of 18 6. Valve Mechanics and Technology In any 6. Valve shunt assembly, Mechanics the valve is the most important component because it regu- and Technology lates In whenany the shunt CSF flow starts assembly, and stops the valve and itimportant is the most changes component the amountbecause of CSFitfluid that regulates passes through the shunt when intracranial pressure (ICP) is when the CSF flow starts and stops and it changes the amount of CSF fluid that passes high. DPV can be classified according through thetoshunt the when mechanical design intracranial in slit, pressure (ICP)miter, is high.diaphragm, DPV can beorclassifiedspring-loaded accord- “ball-in-cone” valves [22]. Most of the first generation and current ing to the mechanical design in slit, miter, diaphragm, or spring-loaded “ball-in-cone” DPV valves use the properties valves [22].ofMost the silicone elastomers of the first generation andandare current of threeDPV different valves families: use the(1) slit, (2) miter, properties of the or (3) diaphragm silicone elastomers valves and are [22]. of Slit three valves are families: different silicone tubes closed (1) slit, at one (2) miter, enddiaphragm or (3) that have small valvescuts [22].orSlit slits in their valves are wall (Figure silicone tubes5A). When closed fluid at one endpressure that have inside smallthe catheter cuts or slitsex- in ceeds the predefined OP, which depends on the stiffness and their wall (Figure 5A). When fluid pressure inside the catheter exceeds the predefined the thickness of the tubeOP, wall, whichthe slits open depends andstiffness on the CSF willand flowthe[22]. The Chabbra thickness TM “slit n’ spring” valve (Surgi- of the tube wall, the slits open and CSF wear Limited, Shahjahanpur, will flow [22]. The Chabbra India) TM is a low-cost shunt “slit n’ spring” valve (Surgiwearin which the slit valve Limited, is protected Shahjahanpur, by a stainless India) steel shunt is a low-cost springin[23] (Figure which 6). valve the slit A miter valve is by is protected basically a silicone a stainless tube that steel spring [23] converges (Figure 6).into opposed A miter valveleaflets that opens is basically whentube a silicone the that pressure differential converges exceeds the into opposed OP leaflets of theopens that valve,whenwhich, theaspressure in all silicone elastomers, differential exceeds depends the OP on size, shape, of the valve, which, thickness, as in all and length silicone of the leaves elastomers, [22]. The depends on theUltraVS™ Valvethickness, size, shape, (Natus Medical and lengthIncorporated, of the leaves USA) is [22]. an example of a miter valve. Diaphragm valves use flexible The UltraVS™ Valve (Natus Medical Incorporated, USA) is an example of a miter valve.silicone membranes mounted in a plastic or Diaphragm metaluse valves seatflexible upon which silicone the diaphragmmounted membranes is movedinby pressure a plastic ordifferences metal seat (Figure upon which 5B). When pressure differential the diaphragm is moved byispressure above the nominal valve differences (Figure OP, theWhen 5B). diaphragm pressure is displaced, differentialand CSF flows is above around the the nominal diaphragm; valve when the pressure OP, the diaphragm is below is displaced, andthe CSF OP, the flows around the returns diaphragm diaphragm;to its when originaltheposition pressureand is below closes thethe OP, the diaphragm valve’s outlet [22]. returns The Con- to its original position and closes the valve’s outlet [22]. The tour-Flex™ valve (Natus Medical Incorporated, Middleton, WI, USA) is a typical dia- Contour-Flex™ valve (Natus Medicalvalve. phragm Incorporated, Middleton, WI, USA) is a typical diaphragm valve. Figure 5. (A). Schematic drawing of a silicone slit valve. Slit valves are essentially silicon tubes that are closed at the end and have slits in their sides. On the left, a closed tube with a lateral slit is shown. On the right, the slit opens and allows CSF Figure 5. (A). Schematic drawing of a silicone slit valve. Slit valves are essentially silicon tubes that are closed at the end flowhave and when theinpressure slits inside their sides. Onthe thetube left,exceeds a closedthe predefined tube OP setting with a lateral definedOn slit is shown. by the the right, manufacturer. Arrows the slit opens andindicate allows the direction of CSF flow. (B). On the left, an opener miter valve is shown. The two silicon leaflets CSF flow when the pressure inside the tube exceeds the predefined OP setting defined by the manufacturer. Arrows open when CSF inside in- the shunt dicate the exceeds directiontheof predefined OP.On CSF flow. (B). (B).the Onleft, the an right, a drawing opener of a diaphragm miter valve valvetwo is shown. The is shown. When CSF silicon leaflets openinwhen the circuit CSF inside exceedsthe shunt the OP ofexceeds the the the valve, predefined diaphragm OP.moves (B). On the right, down a drawing and allows of a to the fluid diaphragm valveArrows pass through. is shown. When indicate theCSF in the direction circuit exceeds of the flow. the OP of the valve, the diaphragm moves down and allows the fluid to pass through. Arrows indicate the direction of the flow. J. Clin. J.J. Clin. Clin. Med. Med. Med. 2021, 2021, 2021, 10,10, 10, x FOR 1210 x FOR PEER PEER REVIEW REVIEW 8 18 88 of of of 19 19 Figure Figure Figure 6. 6. (Left). 6. (Left). (Left). The TheThe Chabbra Chabbra Chabbra TM TM “slit n’ spring” valve (Surgiwear Limited, Shahjahanpur, India) is a design based in the TM “slit “slit n’ n’spring” spring”valve valve(Surgiwear (SurgiwearLimited, Limited, Shahjahanpur, Shahjahanpur, India) is aisdesign India) based a design in the based in slit the slit valve. valve. slit valve. In this In this In this case, case,case, the silicone the silicone the silicone tube tube tube within within within the thethe flushing flushing flushing reservoir reservoir reservoir in whichin in which which the the slitthe isslit slit seat seat seat is is protected protected protected byby a stainless-steel a stainless-steel by a stainless-steel spring. spring.The spring. The redarrowarrowindicates indicates thedirection directionof ofthetheflow. flow.(Right). (Right).Radiograph Radiographof ofaTMaCodman–Hakim Codman–Hakim TM Precision red arrowred directionthe TM Precision The indicates the of the flow. (Right). Radiograph of a Codman–Hakim Precision low-medium DPV low-medium low-medium DPV DPV (Integra (Integra LifeSciences LifeSciences Corporation). Corporation). This This DPVDPV is is a a conventional conventional mechanical mechanical spring-loaded spring-loaded ball-in-cone ball-in-cone (Integra LifeSciences Corporation). This DPV is a conventional mechanical spring-loaded ball-in-cone valve. The three dots valve. valve. TheThe three three dots dots indicate indicate thethe OPOP of of thethe valve valve andandthethe short short arrowhead arrowhead thethe direction direction of of thethe flow. flow. indicate the OP of the valve and the short arrowhead the direction of the flow. Spring-loadedball-in-cone Spring-loaded ball-in-conevalves valves useusea acompletely completelydifferent differentapproach approachtotoregulate regulate Spring-loaded ball-in-cone valves use a completely different approach to regulate pres- pressure. pressure. These These valves valves incorporate incorporate a metallic a metallic spring that exerts the manufacturer’s pre- sure. These valves incorporate a metallic springspring that exerts that exerts the manufacturer’s the manufacturer’s predefinedpre- defined defined force to a synthetic ruby ball located in a cone-shaped orifice [22]. When the dif- force to aforce to a synthetic synthetic ruby ballruby ball in located located in a cone-shaped a cone-shaped orifice orifice [22]. When[22].theWhen the dif- differential ferential pressure ferential exceeds pressure pressurethe exceeds exceeds the OP threshold the OP threshold OP threshold of the valve, of the valve, of the valve, ruby ball the ruby theisruby pushed ball is ball againstpushed is pushed against the against spring the spring and opens the outlet to allow flow (Figure 7). Conventional and opens the outlet to allow flow (Figure 7). Conventional ball-in-cone DPV valvesDPV the spring and opens the outlet to allow flow (Figure 7). Conventional ball-in-cone ball-in-cone DPV are thevalves valves are Codman-Hakim the Codman-Hakim TM are the Codman-Hakim TM Precision Fixed TM Precision Fixed pressure valve (Integra LifeSciences Precision pressure Fixed valvepressure (Integra valve (Integra Corporation, LifeSciences LifeSciences Corporation, Corporation, Plainsboro, Plainsboro, NJ,Plainsboro, USA) and the NJ, NJ, USA)and USA) miniNAV and ® (B. thethe miniNAV miniNAV Braun ® (B. Braun Melsungen AG, Ger- ® (B. Melsungen Braun MelsungenCompared AG, Germany). AG, Ger- to many). many). silicone Compared Compared totosilicone siliconevalves, valves, ball-in-cone valves,ball-in-cone valves ball-in-cone have a morevalvesvalveshave precise have OP a amore and more precise precise sustain OP higher OP and CSFand sustain sustain protein higher higher levels CSF CSF before protein protein becoming levels levels before before clogged than becoming becoming do silicone clogged clogged valves.thanthan dodo silicone silicone Independent valves. valves. studies In-In- have dependent dependent shown studies that,studies have shown have ball-in-cone in general, that, shown that, valves in general, in general, ball-in-cone haveball-in-cone valves valves have better mechanical have better mechan- better mechan- characteristics than ical ical silicone characteristics characteristics valves and than than show asilicone silicone valves bettervalves convergenceandand show show a better a better of pressure–flow convergence convergence performance ofof pressure–flow pressure–flow when tested in performance vitro [20,24].when performance whentested Despite tested ininvitro the frequently vitro[20,24]. [20,24]. seen notionDespite thefrequently frequently that ball-in-cone Despite the valves seen seen notion “arenotion less pronethat that to ball-in-cone the effectsvalves ball-in-cone valves “are of the aging “are less less prone of materials prone to theto the effects thaneffects are miter of of thethe aging oraging of slit valves” materials than [22], asthan of materials far as are arewe miter know, miter oror slitslit this valves” has valves” [22], not [22], yet asas been far asaswewe farproved. know, know, this this hashas not not yetyet been been proved. proved. Figure 7. (Left): Figure Schematic drawing of of a spring-loaded ball-in-cone mechanical valve. Arrow shows thethe direction of of the Figure 7. 7. (Left): (Left): Schematic Schematic drawing drawing a spring-loaded of a spring-loaded ball-in-cone ball-in-cone mechanical mechanical valve. valve. Arrow Arrow shows shows direction the direction of thethe flow. flow. (Right): flow. (Right): (Right): Figure Figure Figure 22 of of the 2 of patent thethe patent patent filed filed by filed S. bybyS. Hakim S. Hakim Hakim [25] with [25] [25] aa detailed with with drawing a detailed detailed drawing drawing of the of of valve thethe valve valve that the that that patent thethe patent patent describes describes describes as as as “a pair of spring operated ball-type check valves made of metal or other relatively inert and non-toxic material not af-af- “a “a pair pair of of spring spring operated operated ball-type ball-type check check valvesvalves made made of of metal metal or or other other relatively relatively inert inert and and non-toxicnon-toxic material material not not affected by fected fected byby temperatures temperatures temperatures in in thethe in the surgical surgical sterilization surgical sterilization range. range. range. sterilization The twin TheThe twin valves twin valves are areare arranged valves arranged in in in series arranged to series faceto series into face the face in in same thethe same direction same di-di- rection rection (outlet of (outlet (outlet one of of oneone adjacent toadjacent adjacent to to the inlet ofthe the inlet inlet the of of thethe other)” other)” other)” [25]. [25]. [25]. AllAll All ofof of the thethe silicone-based silicone-based silicone-based valves valves valves have have have the thethe viscoelastic viscoelastic viscoelastic properties properties properties ofof of the the the silicone silicone silicone elas- elas- elas- tomers; tomers; therefore, therefore, agingaging of of these these materials materials may may significantly significantly alter tomers; therefore, aging of these materials may significantly alter their performance. alter their their performance. performance. How- However, ever, degradation However, degradation degradation and and calcification and calcification ofof of silicone calcification silicone catheters silicone catheters with with catheters with deterioration deterioration ofof of their deterioration their me- their mechanical chanical properties, properties, predisposition predisposition to to catheter catheter fractures, fractures, and and migration migration mechanical properties, predisposition to catheter fractures, and migration of the different of of the the different different parts parts parts ofof of the thethe shunts shunts shunts have have have beenbeen been reported reported reported only only onlyforforfor catheters catheters catheters that that are that inare are inin direct direct contact contact direct with withwith contact the subcutaneous the the subcutaneous subcutaneous tissue [26] tissue but tissue[26]not [26]butinnot but theinsilicon not in thethe slits, miters, silicon silicon slits, slits, and diaphragms miters, miters, andand enclosed diaphragms diaphragms inside enclosed enclosed the housing inside the of the housing valve. of inside the housing of the valve.the valve. 7. 7. Fixed FixedVersus Versus Adjustable AdjustableValves Valves 7. Fixed Versus Adjustable Valves Since the Since theearly early1990s, 1990s,most most manufacturers manufacturers have have produced both produced bothvalves valveswith withfixed fixedOP Since the early 1990s, most manufacturers have produced both valves with fixed OP OP andand adjustable adjustable (“programmable”) (“programmable”) valves valves in which the OP settings can be modified and adjustable (“programmable”) valves inin which which the the OPOP settings settings can can bebe modified modified non- non- J. Clin. Med. 2021, 10, 1210 9 of 18 noninvasively. The first available commercial adjustable valve (AV) was patented by Hakim in 1986 [27]; it is known today as the Codman–Hakim® programmable valve (Integra LifeSciences Corporation). The Codman–Hakim® is one of the best available adjustable valves, but it is also a good example of the limitations of such valves. In the earliest Hakim adjustable valve, the OP could be adjusted to 18 settings in small increments of 10 mmH2 O by the application of an external magnetic field [27]. The most recent version of this valve allows adjusting the OP between 30 and 200 mmH2 O (Integra LifeSciences Corporation). There is still a fundamental misunderstanding of the reasons Hakim thought that an AV was required to manage hydrocephalus. AVs were not introduced for controlling shunt overdrainage, which is the wrong strategy for avoiding it, but to modify the OP to normalize the changes that an implanted shunt induces in ventricular size, IVP, and subdural stress [28–30]. In brief, Hakim biomechanically modeled the brain as an “open cell sponge” in which the venous blood and the extracellular fluid within the brain parenchyma can change their volume because both are connected to the extracranial venous system, which is in turn exposed to the atmosphere [29]. As stated by Hakim, when the ventricles increase their size in hydrocephalus, “the collapsibility of these compartments account for the bioplastic deformation of brain tissue” [29]. According to Hakim’s hypothesis, the part of the IVP that is not absorbed by the brain parenchyma is transmitted to the subdural space and is referred as subdural stress. Its magnitude is directly related to the ventricular size, and Hakim considered it one of the most important factors in hydrocephalus development [31]. In his words, once a shunt is implanted and “as soon as normal ventricle size has been reached, shunt revision should be made to raise CSF pressure in order to prevent further shrinkage of the ventricles”. The update of the OP and therefore of the IVP should restore subdural stress to normal [31]. Despite Hakim’s compelling theory, which pushed AV into the market, as far as we know, no clinical report has been published regarding this management technique. Today, most neurosurgeons choose AV in iNPH patients for three main purposes: (1) controlling overdrainage by increasing the OP, (2) reducing the OP when improvement does not occur, and (3) partially closing the shunt to manage subdural effusions. However, as is discussed elsewhere, the use of AV for managing overdrainage is a mistaken strategy and, as Aschoff remarked, users that select it “can select different grades of over-drainage only, but not avoid it” [1]. In essence, any AV is a DPV with a variable OP. Therefore, these valves will open when PPshunt is >0; however, when patients assume a standing or sitting position, the gravitational-induced HP will overcome the OP even at the highest OP settings (200 mmH2 O = 14.7 mmHg). As described by Meier and Kintzel, they will “remain open too long when the patient moves into the upright position. In this way they could induce suction on the already atrophic brain” and therefore expose the iNPH patient to the adverse events induced by shunt overdrainage [32]. The reasons most patients with simple DPV tolerate chronic overdrainage are discussed in another paper of this Special Issue. Some AV designs, such as the Codman–Hakim® programmable valves, are sensitive to magnetic fields and therefore require routine reprogramming when an MRI is per- formed (Figure 8). Unintended changes in AV valve settings also occur when relatively low-intensity magnetic fields, such as those generated by tablet devices, cell phones, head- phones, metal detectors, and others, are too close to the AV [33]. Many manufacturers have introduced “brakes” in their recent AV models to avoid unintentional reprogramming when the valves are exposed to magnetic fields [34]; however, these new valves generate important neuroimaging distortions (Figure 8), are expensive, and have not been tested in modern high-field magnetic field imaging (MRI) above 3 T. “gravitational-control” devices. These “siphon-controlling” devices were introduced ini- tially in 1973 by Portnoy et al. to reduce the incidence of subdural hematomas and effu- sions that are a consequence of shunt-induced subatmospheric intraventricular pressure J. Clin. Med. 2021, 10, 1210 10 of 18 due to the “shunt acting as a siphon, whose lower end vents to the atmosphere via the heart or peritoneal cavity at a significant distance below the foramen magnum” [35]. Figure Figure 8. This 8. Thisgirl 13-year-old 13-year-old had surgery girl forhad surgery a Chiari for a Chiariwith 1 malformation 1 malformation hydrocephalus. with Shehydrocephalus. She had a Hakim programmable had a Hakim programmable valve implanted with an OP of 70 mmH2O. The patient was scanned valve implanted with an OP of 70 mmH2 O. The patient was scanned in a 1.5 T MRI for control (A,B). In (A), the ventric- in a 1.5 T MRI for control (A,B). In (A), the ventricular size was normal. Arrows show the magnetic ular size was normal. Arrows show the magnetic artifact produced in the different MR1 sequences that was moderate artifact produced in the different MR1 sequences that was moderate in T2-weighted images and in T2-weighted veryimages strongand in thevery strong in the diffusion-weighted diffusion-weighted sequences sequences (B). The patient’s(B). Thewas valve patient’s valve was accidentally accidentally repro- reprogrammed by the doctor grammed by theon call toon doctor ancall OP to of an 150OP mmH O immediately of 2150 after the MRI. mmH2O immediately afterShe thewas MRI.admitted She wasthree ad-days later because of headache and days mitted three drowsiness. The CT later because of scan on admission headache (C) showed and drowsiness. The aCTsignificant increase in(C) scan on admission the ventricular size. showed The OP of thea valve significant increase intothe was readjusted 70 ventricular mmH2 O. The size. The OP patient of the valve improved was and the readjusted new CT scan toat 70 mmH2O. discharge The in (D). is shown patient improved and the new CT scan at discharge is shown in (D). However, the lack of available evidence proving the superiority of AV does not al- low us to recommend These “antisiphon” adjustable over devices, independently of howconventional DPV for managing they work—antisiphon devicesNPH patients. This applies onlyaccessories—are or gravitational-compensating to DPV alone and not toinDPV discussed withpaper another any additional in this Special“antisiphon” or “gravitational-control” Issue. In our opinion, the combinationdevices. of both These DPV in“siphon-controlling” series with devices to devices controlwere shunt introduced ini- tially in 1973 by Portnoy et overdrainage when patients are standing should beal. to reduce the standard of care in most patients and effusions incidence of subdural hematomas that are a consequence of shunt-induced subatmospheric with hydrocephalus. However, to discuss the rationale for this recommendation intraventricular pressure due to is be- yond the scope theof“shunt acting this paper. In as a siphon, brief, in vitrowhose studieslower haveend vents shown to antisiphon that the atmosphere devicesvia the heart or (ASD) reduceperitoneal cavity at a significant shunt overdrainage induced bydistance below the foramen the posture-increase magnum”pres- in hydrostatic [35]. sure when patientsThese “antisiphon” are standing devices, or sitting independently [34,36]. In addition, some of how they work—antisiphon clinical studies have devices or gravitational-compensating accessories—are discussed clearly shown that ASD reduce the number of adverse events in patients with iNPH and in another paper in this Special Issue. In our opinion, the combination indirectly improve their clinical outcome [37–39]. of both DPV in series with devices to control shunt overdrainage when patients are standing should be the Despite the lack of evidence, the guidelines for the treatment of iNPH published in standard of care in most patients 2005 concluded with hydrocephalus. that However, to “several retrospective discuss studies the rationale suggest for this recommendation that adjustable (“program- is beyond mable”) valves theoffer scopeanofadvantage this paper. over In brief, fixed in valves vitro studies because have shown that corrections forantisiphon under- ordevices (ASD) reduce shunt overdrainage induced by the posture-increase overdrainage, which are encountered relatively frequently with iNPH, can be performed in hydrostatic pressure when noninvasively instead of requiring a surgical revision” [40]. However, all the studies re- have clearly patients are standing or sitting [34,36]. In addition, some clinical studies ported in the shown that ASD reduce 2005 guidelines the number of were retrospective adverse and do not events in patients support with iNPH and indirectly this recommenda- improve their clinical outcome [37–39]. tion when the Grading of Recommendations Assessment, Development and Evaluation Despite the lack of evidence, the guidelines for the treatment of iNPH published in (GRADE) working group criteria for evaluating the quality of evidence are applied [41]. 2005 concluded that “several retrospective studies suggest that adjustable (“programmable”) Since the guidelines for the treatment of iNPH were published, some papers have eval- valves offer an advantage over fixed valves because corrections for under- or overdrainage, uated the use of AV with or without antisiphon devices and have tried to compare pa- which are encountered relatively frequently with iNPH, can be performed noninvasively tients with a gradual reduction of the valve OP vs. a fixed OP [38,42] or the optimal OP instead of requiring a surgical revision” [40]. However, all the studies reported in the 2005 guidelines were retrospective and do not support this recommendation when the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group criteria for evaluating the quality of evidence are applied [41]. Since the guidelines for the treatment of iNPH were published, some papers have evaluated the use of AV with or without antisiphon devices and have tried to compare patients with a gradual reduction J. Clin. Med. 2021, 10, 1210 11 of 18 of the valve OP vs. a fixed OP [38,42] or the optimal OP setting for these valves [43]. However, the design of these studies and/or their methodology precludes extracting solid conclusions from them. In high-income countries, AVs double the cost of a fixed valve from the same manu- facturer. However, in low- and medium-income countries, AVs have a significantly higher cost—in some countries, outrageously overpriced—than fixed valves, and therefore AVs are not affordable. However, despite the lack of robust evidence about their benefits, and when cost is not a relevant variable, it is important to take into consideration that AVs allow us to fine-tune the OP in many pediatric and adult patients with hydrocephalus and might reduce the number of shunt revisions. 8. The Resistance of Shunts and Valves: A Neglected Variable Up to this point, we discussed how DPV valves open and close and the effect of the PPshunt in regulating CSF flow. However, from Equation (2) it is obvious that when the valve in a shunt is opened, CSF flow is regulated by both PPshunt and Rshunt . Interestingly, Rshunt is never reported by shunt manufacturers, and is available only from independent laboratories typically supported by research grants or academic institu- tions [44]. In Europe, the first independent laboratory that tested shunts was led by Aschoff in Heidelberg [45], and in the last 20 years, the most significant contributions have been made by the Cambridge Shunt Evaluation Laboratory, which conducted independent tests of all shunts available in the UK. The results were initially published by the Medical Devices Agency in the “blue reports” [20], but the Cambridge Laboratory has continued to publish independent evaluation for at least 26 commercially available shunts in peer-reviewed journals [44]. For a better understanding of the relevance of Rshunt in the management of hydro- cephalus, in Figure 9 we plotted the maximum estimated flow of water through a constant 100 cm length silicone tube with a variable internal diameter (ID) of 0.40–1.20 mm at a DP from 0 of 60 cmH2 O (0–44 mmHg). Most manufacturers provide distal catheters with an ID between 1.0 and 1.40 mm for VP/VA shunts, and some LP designs have catheters with an ID of 0.50–0.80 mm. As shown in this figure, following Poiseuille’s law, flow through a constant tube length decreases as internal diameter decreases. For the sake of clarity, let us assume the estimated shunt flow in a real patient in whom all the variables that intervene in the regulation of DPV are known. This 72-year-old male had a nine-month history of gait disturbance, urinary incontinence, and nondetectable cognitive impairment. The patient’s height was 173 cm and his weight 82 kg (body mass index (BMI): 27.4, moderate overweight). ICP monitoring showed a mean ICP of 8 mmHg with ~40% high- and low-amplitude B-waves—wave amplitude > 10 or ≤ 10 mmHg, respectively—compatible with the diagnosis of iNPH [46]. If a neurosurgeon decided to implant in this patient a 100 cm length valveless silicone tube of 1.20 ID, the maximal possible CSF flow through the shunt when the patient is recumbent—assuming an IPP of 2 mmHg and a PPshunt = 6 mmHg—would be ~209 mL/h. When this shunted patient stands (Figure 3), IVP is reduced to 0 mmHg or even to moderate negative values [47]. If we assume a gravitational-induced HP of 70 cmH2 O (51 mmHg) when the patient is standing, the CSF flow could increase to a maximum of 1700 mL/h. In this simulated scenario, the patient exceeds the physiological production of CSF (~20 mL/h, 500 mL/ 24 h). In this situation, the cerebral ventricles will rapidly collapse, and the patient would be exposed to all the complications of shunt overdrainage. If another neurosurgeon had decided to implant a valveless silicone tube of the same length but with an ID of 0.60 mm (Figure 9), the same patient would have drained only 13 mL/h when recumbent, a value below the normal CSF production. However, when the patient is standing, the shunt will overdrain to a maximum CSF flow of 170 mL/h. J. Clin. J. Clin. Med.Med. 10,10, 2021, 2021, 1210 PEER REVIEW x FOR 12 of 18 12 of 19 Figure 9. Estimated in vitro flow through silicon tubes of 100 cm constant length and with an inner Figure 9. Estimated in vitro flow through silicon tubes of 100 cm constant length and with an inner diameter (ID) varying from 0.4 to 1.2 mm at different differential pressures (DPs) (0–60 cmH2 O; diameter (ID) varying from 0.4 to 1.2 mm at different differential pressures (DPs) (0–60 cmH2O; 0–44 mmHg). The reader can replicate these data by using the online calculator provided by vCalc™ 0–44 mmHg). The reader can replicate these data by using the online calculator ◦provided by (http://bit.ly/2Y9FEss) and considering that the viscosity of water at a temperature of 37 C is vCalc™ (http://bit.ly/2Y9FEss) and considering that the viscosity of water at a temperature of 37 °C 0.69 mPa-s [48]. A tube with an ID of 1.2 mm has a theoretical Rshunt of 1.72 mmHg/mL/min, of is 0.69 mPa-s [48]. A tube with an ID of 1.2 mm has a theoretical Rshunt of 1.72 mmHg/mL/min, of 2.43 mmHg/mL/min when the ID is decreased to 1.1, and of 139 mmHg/mL/min when the ID 2.43 mmHg/mL/min when the ID is decreased to 1.1, and of 139 mmHg/mL/min when the ID is 0.40 is 0.40 mm. At a DP of 60 cmH O, the maximum flow for each tube will increase from 19 mL/h mm. At a DP of 60 cmH2O, the2 maximum flow for each tube will increase from 19 mL/h for a tube for a tube with an ID of 0.4 to 1539 mL/h for a tube with an ID of 1.2 mm. The reader needs to be with an ID of 0.4 to 1539 mL/h for a tube with an ID of 1.2 mm. The reader needs to be aware that aware that theoretical estimates in Rshunt reported here can differ from some published results on theoretical estimates in Rshunt reported here can differ from some published results on bench tests. bench tests. Theoretical estimates may differ from results on tubes conducted in test rigs because of Theoretical estimates may differ from results on tubes conducted in test rigs because of differences differences in the catheter length, presence of air bubbles, experimental temperature, composition of in the catheter length, presence of air bubbles, experimental temperature, composition of the in- the infused fluid, and characteristics of the flow (pulsatile vs. steady). fused fluid, and characteristics of the flow (pulsatile vs. steady). Based on this basic hydrodynamic principle, Sotelo, a Mexican neurosurgeon, intro- ducedBased in 1993ona low-cost this basic hydrodynamic valveless principle, shunt for managing Sotelo, patients a Mexican with neurosurgeon, hydrocephalus [49,50]. in- troduced In the most inrecent 1993 version, a low-cost valveless Sotelo’s shunt fora ventricular shunt comprises managingcatheter, patientsa connector, with hydrocephalus and a 100 cmIn [49,50]. length distal catheter the most with an IDSotelo’s recent version, of 0.51 mm opened shunt at its enda[49]. comprises The rationale ventricular catheter, a underlying this simple design is twofold: (1) to avoid the intermittent connector, and a 100 cm length distal catheter with an ID of 0.51 mm opened at its end on–off working of DPV [49]. Thevalves and underlying rationale to allow for thisa continuous simple designCSF flow, and (2) (1) is twofold: to reduce to avoid hydrostatic- the intermittent induced overdrainage when the patient is standing [51]. According to Sotelo, the CSF on–off working of DPV valves and to allow for a continuous CSF flow, and (2) to reduce flow though this simple tube is close to the constant production of CSF (~0.35 mL/min, hydrostatic-induced overdrainage when the patient is standing [51]. According to Sotelo, 21 mL/h) with modest variations in flow imposed by the gravity-induced HP generated the CSF flow though by postural changes [51]. thisSotelo’s simpleshunt tubecan is close to the constant be considered as a simple production of CSF (~0.35 “flow-regulated” mL/min, 21 mL/h) shunt. Valveless withshould shunts modest variations be used only inin flow circumstances special imposed by the gravity-induced in which they can HP generated by postural play an important changesin [51]. role, especially treating Sotelo’s isolatedshunt can bemulticompartmental IV ventricles, considered as a simple “flow-regulated” hydrocephalus, isolatedshunt.CSFValveless shunts collections, or inshould bearachnoidal treating used only in special cysts. circumstances However, neu- in rosurgeons which they using themanneed can play to knowrole, important the relevance especially of in thetreating ID to avoid both shunt isolated under- mul- IV ventricles, and overdrainage. hydrocephalus, isolated CSF collections, or in treating arachnoidal ticompartmental cysts.The previous examples reflect the need to consider the resistance of all the components However, neurosurgeons using them need to know the relevance of the ID to avoid of a shunt assembly and, ideally, to have, at least, good estimates of the IVP and IPP when both shunt under- and overdrainage. managing individual patients with iNPH. Rshunt and Rvalve are not provided by most shunt The previous suppliers examples and they need reflect the to be estimated fromneedtheto consider the flow–pressure resistance data providedof(Figure all the4).compo- nents of a this However, shunt assembly neglected and,defines variable ideally, theto have, shunt atwhen flow least,PP good shunt estimates is ≥0 mmHg,of theandIVP and IPP when managing individual patients with iNPH. R and R therefore is an essential information that neurosurgeon should have. This was clearly shown shunt valve are not provided by most in theshunt seminal suppliers and they but undercited paperneed to bebyestimated published Rayport and fromReisstheinflow–pressure 1969 [14], in whichdata pro- vided (Figure 4). However, this neglected variable defines the shunt flow when PP shunt is ≥0 mmHg, and therefore is an essential information that neurosurgeon should have. This was clearly shown in the seminal but undercited paper published by Rayport and Reiss in 1969 [14], in which they reported a 17-month-old girl with a communicating J. Clin. Med. 2021, 10, 1210 13 of 18 they reported a 17-month-old girl with a communicating hydrocephalus deteriorating to a coma and who recovered after the insertion of an external ventricular drainage. The CSF outflow in this girl exceeded 1000 mL/24 h at an OP of 175 mmH2 O (12.8 mmHg) [14]. In this patient, a Pudenz–Heyer ventriculo-atrial shunt was implanted with a CP of 70 mmH2 O (5.1 mmHg), but the external ventriculostomy was maintained for controlling the CSF output. The patient deteriorated again after surgery, and the CSF outflow at neuroworsening was above 25 mL/h despite a functional shunt. To manage this problem, the girl required a second Pudenz–Heyer shunt implanted in parallel to drain the excessive CSF production that a single shunt was unable to manage [14]. In a second part of their study directed toward understanding the problem they faced treating this unusual case, Rayport and Reiss designed an in vitro setup in which they tested the hydrodynamic profile of three different valves (Spitz–Holter, Pudenz–Heyer, and Cordis–Hakim) with the same reported nominal CP range [14]. The pressure–flow results shown in their Figure 4 (page 464 of the manuscript) showed significant differences in the hydrodynamic behavior and significant difference in the maximum flow rate achievable by the three DPVs. In brief, Rayport and Reiss showed that the Rshunt of the three similar medium-pressure DPVs were significantly different: 2.4 mmHg/mL/min for the Cordis– Hakim, 4.2 for the Pudenz–Heyer, and 16.6 mmHg/mL/min for the Spitz–Holter (values estimated by us from the Figure 4 of the manuscript) [14]. 9. Hydrodynamic Properties of Different Shunts The relevance of the Rshunt in the literature, raised indirectly by Rayport and Heiss’s seminal paper, was largely neglected in the neurosurgical literature and reassessed only after the studies of independent bodies such as the Aschoff and Cambridge shunt laborato- ries were published [24,52]. Czosnyka et al., in their original “blue cover reports” and in subsequent studies, defined valve hydrodynamic resistance as the regression line obtained in pressure–flow tests [24]. In their comprehensive reports, they have shown that most DPVs have an Rshunt much lower (<2–5 mm Hg/mL/min) than the normal physiological values quantified by infusion tests, which are in the range 6–10 mmHg/mL/min [24]. In Table 1, we summarize the Rshunt values of some DPVs with and without the distal catheter attached, using the results reported by the Cambridge Shunt Laboratory in various publications [20,24,53–57]. The single most important caveat for neurosurgeons managing patients with iNPH is that most shunt devices available have a low Rshunt even with the attached distal catheter, and therefore overdrainage will be induced depending on the variables already discussed. A second message is that different valves included by manufacturers in the same category (i.e., medium-pressure DPVs) have variable OP and significantly different hydrodynamic profiles that should be known when managing difficult cases or reconsidering shunt revision in nonresponsive iNPH patients in which shunt underdrainage is suspected. 10. DPV and Shunt Assemblies for Complex Hydrocephalus Patients Patients with hydrocephalus are a heterogeneous population. In their management, there is a subgroup of complex cases in which an adequate shunt selection and in-series or integrated devices (i.e., antisiphon or gravitational-control devices) are much more relevant than in conventional patients to reduce the risk of overdrainage and shunt malfunction, and to improve their outcome. Some cases of pediatric hydrocephalus or iNPH, post- traumatic hydrocephalus and the entity defined by Oi in 1996 named long-standing overt ventriculomegaly in adults (LOVA) [60] are some of these cases [61–63]. In brief, LOVA is a type of hydrocephalus that develops during childhood, but where symptoms appear during adulthood and in most patients is associated with aqueductal stenosis, massive ventriculomegaly, and macrocephaly [61]. Many have a clinical presentation compatible with NPH syndrome [61]. J. Clin. Med. 2021, 10, 1210 14 of 18 Table 1. The information shown in this table regarding resistance was extracted from different papers and reports published by the UK Shunt Evaluation Laboratory and not from the information provided by manufacturers [53]. When not available from independent studies, CP reflects the manufacturer information. Sotelo’s shunt data are from Sotelo et al. [51,58]. The hydrodymanic profiles of silicone tubes are calculated with the online calculator provided by vCalc™ (http://bit.ly/2Y9FEss, accessed on 1 September 2020) and considering that the viscosity of water at a temperature of 37 ◦ C is 0.69 mPa-s. CP: closing pressure in mmHg. Rvalve : static resistance of the valve calculated from pressure–volume tests and measured in mmHg/mL/min. Rshunt : total resistance of the shunt as provided by the manufacturer that includes the Rvalve and the distal catheter provided by the manufacturer attached. Delta valve (Medtronic Medical Devices, Minneapolis, MN, USA) have two performance levels (PL1 and PL2) [59]. The values refer to the Rvalve without the siphon-controlled device active [53]; Codman–HakimTM (Integra Lifesciences, Plainsboro, NJ, USA) [20]; Polaris (SOPHYSA, Orsay, France). CP Rvalve Rshunt Model (mmHg) (mmHg/mL/min) (mmHg/mL/min) Silicone 100 cm (1.2 mm ID) 0 No valve 1.72 Silicone 100 cm (1.0 mm ID) 0 No valve 3.57 Silicone 100 cm (0.6 mm ID) 0 No valve 27.5 Sotelo’s shunt (0.51 mm ID) 0 No valve 52.7 Codman–Hakim (low) 2.9 1.65 4.92 Codman–Hakim (medium-low) 5.1 1.83 5.10 Codman–Hakim (high) 9.6 2.20 5.46 Delta valve (PL1) 1.9 1.9 3.6 Delta valve (PL2) 4.0 2.2 3.7 Contour Flex (low) 0.7–3.7 2.3 3.5 Contour Flex (medium) 3.7–8.1 2.5 3.8 Contour Flex (high) 8.1–12.5 2.8 4.2 Polaris (30 mmH2 O) 2.2 1.6 4.6 Polaris (70 mmH2 O) 5.14 2.1 5.1 Polaris (110 mmH2 O) 8.1 2.5 5.6 Dual Switch Valve (5 cmH2 O) 3.7 2.2 2.9 Dual Switch Valve (10 cmH2 O) 7.4 2.2 2.9 Most of these complex patients share a significant increase in ventricular size (I. Evans > 0.42) and a significant disproportion between the intracranial and the cerebral volume—with or without macrocephaly. In these patients, ICP monitoring has shown different profiles, but, frequently, these patients have a mean ICP < 12 mmHg [62]. Oi et al. reported that patients with LOVA have a high ICP [61]. However, in the paper by Oi et al., ICP statistics were not presented and their example of a “high ICP” presented in Figure 4 shows a mean ICP of ~12 mmHg, with a train of high amplitude B-waves with peaks around 30 mmHg [61]. This profile is compatible with the most frequent pattern found in iNPH patients and described by Sahuquillo et al. as “compensated hydrocephalus” [46], and also found as the predominant ICP profiles in patients with severe ventriculomegaly and macrocephaly [62]. There is the generalized idea that in these LOVA or LOVA-like patients—severe ventriculomegaly not associated with aqueductal stenosis—the risk of implanting a conventional DPV or even AV is very high. This is based on the daily practice of many neurosurgeons, supported by reports in the literature, where the incidence of subdural hematomas/effusions in these patients is very high [61]. Due to the unusually high risk of complications Oi et al. suggested selecting neuroendoscopic surgery as the initial treatment for LOVA patients [61]. However, in treating LOVA or LOVA-like patients, we support the idea of Kiefer et al. that for these patients the best treatment option is the combination of an AV with a gravita- tional device [64]. In their seminal paper, Kiefer et al. stated that “This study demonstrates that the gravitational shunts—as opposed to conventional DP shunts—can effectively pre- vent over-drainage even in this high-risk group with LOVA hydrocephalus” [64]. Selecting a high OP when treating these patients increases the risk of underdrainage when the patient is recumbent and does not reduce the risk of overdrainage when the patient in sitting or standing. The design and rationale of the different antisiphon devices and their indications are discussed in another paper in this Special Issue. J. Clin. Med. 2021, 10, 1210 15 of 18 11. Conclusions and Recommendations It is obvious that any DPV is unable to control for shunt overdrainage when implanted without any gravitational-control or antisiphon device in patients without a significant increase in the IPP. This topic is discussed in another part of this Special Issue. However, devices to control for postural-induced changes in hydrostatic pressure are not yet generally used in adult and pediatric neurosurgery. To close this review, we would like to give some recommendations for selecting the most appropriate shunt for a patient with iNPH. The reader needs to take into consideration that our recommendations are not evidence-based because of the lack of controlled trials and that they are exclusively based on the quantitative assessment of CSF dynamics and the reports elaborated from independent bodies regarding valves and shunts. We have also incorporated the experience of the senior authors in monitoring many patients with iNPH before and after shunting [65,66]. Although we use these recommendations routinely in the management of iNPH, we cannot demonstrate the relevance of them in modifying the outcome of iNPH patients until tested in adequately designed prospective randomized– controlled trials. However, we believe that these recommendations could be helpful for neurosurgeons to rationalize the management of complex hydrocephalus cases and in avoiding the application of one-size fits all simple solution for a complex problem. • In patients with iNPH and unknown IVP, because ICP is not available or used, it is recommended to use low-pressure valves. The use of these valves will avoid problems with underdrainage when the patient is recumbent. Selecting high-pressure DPVs does not control overdrainage and increases the risk of underdrainage while the patient is recumbent. • Spring-and-ball mechanical valves are much more reliable in OP than are silicone- based valves. In Table 1, we show that the OP can be defined with a narrow limit in mechanical valves, but that manufacturers usually provide ranges of “working pressures” for nonmechanical valves, reflecting the potential variability in OP even in the same lot of valves. • Without gravitational control of the postural-induced hydrostatic pressure, all DPVs, independent of their OP, will overdrain when the patients assume the standing or sitting position. An exception to this rule is when for different reasons—obesity, pregnancy, abdominal distension, etc.—IPP is significantly raised, causing PPshunt to be reduced when the patient is standing. Therefore, neurosurgeons should consider gravitational control—either integrated in the valve or as an added device—in most patients in which DPVs are used. As Czosnyka et al. cautioned, neurosurgeons should take care when implanting “low-resistance shunts” into patients with gross ventricular dilatation or greatly increased cerebrospinal compliance, and of their subsequent mobilization, if no siphon control mechanism is added [24]. • In the selection of DPVs, we recommend knowing the specifications provided by the manufacturer and the hydrodynamic properties of the selected shunt from indepen- dent research. It is important to remember that a high resistance valve together with a catheter of reduced ID increases the risk of nonresponse in iNPH patients. • The most rational approach to selecting the most appropriate shunt for an individual patient is to have the best information concerning shunt hardware and as many patient variables as possible that will influence PPshunt . Apart from height, weight, and BMI, an estimation of the mean ICP and IPP is helpful [67]. • In low- and medium-income countries, AVs are significantly overpriced and therefore not affordable. However, despite the lack of robust evidence about their clinical benefits, and when cost is not a relevant variable, AVs allow us to fine-tune the OP in many pediatric and adult patients with hydrocephalus and might reduce the number of shunt revisions. • An important recommendation for all neurosurgeons involved in the management of iNPH was introduced in the Shunt Book published by Drake and Sainte-Rose: “Even J. Clin. Med. 2021, 10, 1210 16 of 18 if the ideal shunt existed, it would be quickly rendered useless by improper surgical technique during implantation” [6]. Author Contributions: Author contributions to the study and manuscript preparation include the following. Conception and design, M.-A.P., K.R., and J.S.; drafting the article, M.-A.P., K.R., and J.S.; critically revising the article and making substantial contributions, A.A., H.C., D.G., and D.L.- B.; reviewed the submitted version of manuscript, all authors; approved the final version of the manuscript on behalf of all authors, M.-A.P. and J.S. Role of the funder/sponsor: funders had no role in the design and conduct of the study, neither in the collection, analysis, and interpretation of the data nor in the review or approval of the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This work has been supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 675332; Fondo de Investigación Sanitaria (Instituto de Salud Carlos III) grant PI18/00468 and DTS16/00087, cofinanced by the European Regional Development (ERDF); Ministerio de Economía y Competitividad/FEDER (PHOTODEMENTIA, DPI2015-64358-C2-1-R). Acknowledgments: We thank A. Aschoff, Senior Neurosurgeon formerly at the Department of Neurosurgery, University of Heidelberg—Heidelberg, Germany, for his generosity in granting us permission to use some of the images shown in this paper. To Victoria Ramicone, graphic designer for drawing some of the figures shown in this paper. Conflicts of Interest: The authors report no conflict of interest concerning the materials or methods used in this study or the findings and opinions specified in this paper. 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