1015202530CA 02265859 l999-03- 11W0 98/1 1934 PCT/DK97/003921DEVICE FOR THE TREATMENT OF HYDROCEPHALUSThe present invention relates to a cerebrospinal fluid shuntsystem for shunting cerebrospinal fluid from the brain ven-tricles to sinus sagittalis.GENERAL BACKGROUNDCerebrospinal fluid is formed in the ventricular system ir-respective of the intracranial pressure (ICP). The formationrate is constant, with a range of 0.3-0.4 ml/min.and Gjerris 1987).crease in the amount of intracranially located cerebrospinal(BzrgesenHydrocephalus, i.e. a pathological in-fluid, arise when the outflow of the cerebrospinal fluid isobstructed leading to an increase in the intracranial pres-sure and in the amount of intracranially located cerebrospiânal fluid. The obstruction may be localized in the aqueductor the IV ventricle or in the normal resorption sites invilli arachnoidales in connection with the sagittal sinus.Pathoanatomically, hydrocephalus is divided in communicatingor nonâcommunicating hydrocephalus dependent whether there ispassage between the ventricular system and sinus sagittalisor not. Communicating hydrocephalus, which is generallycaused by obstruction located in the villi arachnoidales forexample due to fibrosis formed in response to bleeding in theliquor, is the most common form of hydrocephalus.The treatment of hydrocephalus aims at reducing the intra-cranial pressure to normal, physiological values and therebyalso reducing the amount of cerebrospinal fluid towardsnormal, physiological values. This is obtained by deducting(CSF)another resorption site, bypassing the pathological obstruc-cerebrospinal fluid from the ventricular system totion by use of a CSF shunt. The most suitable diversion sitesfor CSF have been found to be the right atrium of the heartand the peritoneal cavity. Valves have been designed tohinder retrograde flow in the drainage system which couldoccur due to pressure differences between the intracraniall0l5202530CA 02265859 l999-03- 11W0 98/1 1934 PCT/DK97/003922cavity and the resorption site, in connection withe.g.increased chest and/or abdominal pressure in connection withe.g cough or defecation.Until the last 6 years the CSF shunts have been based on theprinciple of maintaining a constant ICP regardless of theflow-rate of CSF.off CSF-flow when the differential pressure between the inletand the outlet ofcalled thebeen necessary in order to maintain a basal ICP due to theThe CSF shunts have been constructed to cutthe CSF shunt was reduced to a predestinedlevel, opening pressure of the shunt. This hasuse of an unphysiological resorption sites located outsidethe intracranial cavity. Example of a such ICP shunt is shownin US 4,904,236 which is a fluid flow control device forcontrolling the flow of fluid from one region of the body tobe drained to another region.Clinical experience has proven that this principle of shunt-Sudden rises of the ICP, e.g.physical exercise, or pathologicaling is not an ideal solution.due to change of position,pressure waves result in excessive CSF drainage. This so-called hyperdrainage leads to subnormal ICP for shorter orlonger periods of time. Several reports in the literature(Aschoff et al., 1995) point at problems due to this hyper-drainage, and especially the pronounced narrowing of theventricles has been pointed out to be the main factor leadingto malfunctioning of the implanted shunting device. Thereason is that the ventricular walls may collapse around the(cells, debris)ventricular CSF shunt device, and particlesmay intrude into the shunt device.This has led to introduction of multiple designs of drains tobe used in the ventricular cavity. An effect of these diffe-rent drain designs on the complication rates of shunts hasnot been proven.In the recent years CSF shunt devices have been introducedwhich aim at regulating the flow rate of CSF, see e.g. US1015202530CA 02265859 l999-03- 11W0 98/1 1934 PCT/DK97/0039234,781,673 which describes a brain ventricle shunt system withflowrate switching means.An alternative flow regulating mechanism of the Orbis Sigmashunt results in partial closure of the shunt at increases inthe differential pressure above 10 mm Hg, and in reopening ofthe shunt when the differential pressure exceeds 35 mm Hg. Ithas been shown that this type of shunt indeed leads to areduction of the complication rate of the system. Anothershunt system, The Pudenz Delta valve, also hinders excessiveCSF outflow at higher pressure levels. US 4,605,395 is anexample of a shunt device comprising a nonlinear hydraulicfilter valve which closes in the event of large changes inflow rate.Still, the above CSF shunt systems drain the CSF to a resorp-tion site that is far from normal and to a site where thepressure difference over the shunt may differ substantiallyfrom the normal, physiological pressure ranges.Occasional reports in the literature have described the useof ventriculoâsuperior sagittal shunts for the treatment of(Hash et al., 1979 and Wen, 1981). In theit is concluded that the describedhydrocephalusarticle by Hash et al.technique wherein a low-low or extraâlow pressure one wayvalve is used may be suitable for patients with high pressurehydrocephalus and of particular value in very ill or debili-tated patients because of the rapidity with which it can beperformed under local analgesia whereas its use in normal orlow pressure hydrocephalus must still be evaluated. Thisarticle is followed by a comment by the editor that there area multitude of remaining critical questions. One of theproblems not addressed in this study is overdrainage due tothe fact that the used valve is not flowârestricting.Wen reports the treatment of fifty-two children with hydro-cephalus with ventriculo-superior sagittal sinus shunts byuse of a modified Pudenz tube. In this tube there is provided1015202530CA 02265859 l999-03- 11W0 98/1 1934 PCTlDK97I003924slits which provide an opening pressure of about 6 mm Hg. Noclear conclusion can be drawn from this report except thatshunting to the sagittal sinus does not inherit seriouscomplications.EP 066 685 describes a drain comprising a bundle of one ormore microtubules, each being about 0.44 mm in diameter forcontrolling hydrocephalus comprising a plurality of pliablemicrotubular members for conducting cerebrospinal fluid fromthe cerebral ventricle to selected areas of the human body,e.g. to the subarachnoid space. Essentially, this patentrelates to a draining system aiming at avoiding obstructiondue to clotting of the draining system and is not flowâreguâlating.SUMMARY OF THE INVENTIONThe device for treatment of hydrocephalus of the inventionleads the CSF from the ventricles to the sagittal sinusbeneath the sagittal suture. The present invention thus pro-vides a CSF shunt system that treats the hydrocephalus bybypassing the pathological obstruction, but diverts the CSFinto its normal resorption site, and the pressure differenceover the CSF shunt system is similar to the physiologicalpressure differences between the ventricles and the resorp-tion site, thus regulating the CSF flow to be within thenormal range and avoiding complications due to hyper drain-age. Where appropriate, the present invention also relates toa method of treating hydrocephalus by use of the cerebroâspinal fluid shunt system of the invention.LEGENDS TO FIGURESFig. 1 shows a cerebrospinal fluid shunt according to anembodiment comprising an antechamber, a flow regulator, and acheck valve connected in series.10152025CA 02265859 l999-03- 11W0 98/11934 PCT/DK97/003925Fig. 2 is a side view of a cerebrospinal fluid shunt accord-ing to a preferred embodiment in which the flow regulatormeans is divided in two parts with the check valve inbetweenthem.Fig. 3 is a top view of the same cerebrospinal fluid shunt.Fig. 4 shows three crossâsections through the check valvewith the ball of the check valve.Fig. 5 shows the cerebrospinal fluid shunt with an antechamâber, a unidirectional check valve and a flow regulating tube,top view.Fig. 6 shows the cerebrospinal fluid shunt in a lateral view.Fig. 7 shows the cerebrospinal fluid shunt in a threeâdimenâsional view.Fig. 8 is a frontal section through sinus sagittalissuperior.Fig. 9 is a sagittal section through sinus sagittalis.Fig. 10 shows the influence of the length on the radius given10 mm Hg/-ml/min and C. 12 mm Hg/ml/min. In these particular examples,a resistance to outflow at A. 8 mm Hg/ml/min, B.the differential pressure is 4 mm Hg and the viscosity is0.0072 dyn*sec/cmzâDETAILED DISCLOSURE OF THE INVENTIONIn normal conditions the CSF is produced in the chorioidplexus in the ventricles. It flows through the ventricles,aqueduct and basal cisterns over the cerebral surface to thearachnoid villi, from where the CSF is absorbed into thesagittal sinus.l0l5202530CA 02265859 l999-03- 11W0 98/1 1934 PCTIDK97/003926From measurements in 333 patients (Bzrgesen and Gjerris 1987)(submitted forpublication)) it has been possible to establish the relation-and 52 normal humans (Albeck, Borgesen et al.ship between CSF production rate (FR), intracranial pressure(ICP), (Pss)tance to outflow of CSFpressure in the sagittal sinus and the resis-(Rout) :ICP = FR * Rout + PS5The relation between the intracranial pressure and the forma-tion rate is linear, and the production rate measured wasfound to be 0.3 ml/min. (Borgesen and Gjerris 1989).The detailed knowledge on CSFâdynamics, obtained in the labo-ratories at the Department of Neurosurgery, Rigshospitalet,Copenhagen, Denmark, has provided the necessary data whichcould make it possible to define a CSF shunt system thatimitates the normal, physiological drainage of CSF. However,until the present invention, it has not been proposed orcontemplated to use this knowledge to design a cerebrospinalfluid shunt system as outlined in the following.The present invention relates to a cerebrospinal fluid shuntsystem comprising brain ventricle catheter means for inser-tion into the brain ventricle so as to drain cerebrospinalfluid from said brain ventricle; sinus sagittalis cathetermeans for insertion into the sinus sagittalis for feedingsaid cerebrospinal fluid into sinus sagittalis; shunt mainbody means connected at one end thereof to said brain ven-tricle catheter means and at another end thereof to saidsinus sagittalis catheter means for providing fluidic com-munication between said brain ventricle catheter means andsaid sinus sagittalis catheter means; and tubular flow pas-sage restricting means defined within said shunt main bodyand fluidically connecting said brain ventricle cathetermeans and said sinus sagittalis catheter means, said tubularflow passage restricting means defining a system total resis-1015202530CA 02265859 l999-03- 11W0 98/1 1934 PCT/DK97/003927tance to flow of 8-12 mm Hg/ml/min. Preferably, the resis-tance to flow is about 10 mm Hg/ml/min.Essentially, the tubular flow passage restricting means forfluidically connecting the brain ventricle and the sinussagittalis could in itself act as a brain ventricle cathetermeans and a sinus sagittalis catheter means thus making theconstruction very simple, the only limiting factor being thatthe device should define a resistance to flow of 8-12 mm Hg/-ml/min.Optionally, the cerebrospinal fluid shunt system further com-prises check valve means disposed within said shunt main bodyfor preventing said cerebrospinal fluid from flowing backfrom said sinus sagittalis catheter to said brain ventriclecatheter.By designing the shunt to exert a substantially constantresistance to outflow at the normal level, and by using thesagittal sinus as the resorption site, the drainage of CSF isregulated by the normal pressure differences between the pro-duction and the resorption sites. Excessive increases of theintracranial pressure are paralleled by increases also in thesagittal sinus, and the CSF outflow through the shunt is im-peded by a resistance in the normal range. Hyperdrainage isthen totally avoided.The innovation is thus to use the recently defined levels ofthe normal resistance to CSF outflow and create a resistanceto CSFâoutflow in the shunt similar to the normal resistance.By using the sagittal sinus as the recipient site, physio-logical increases of the intracranial pressure will notincrease the differential pressure over the shunt. Posture-related changes in the differential pressure as seen inshunts leading the CSF to the right atrium of the heart or tothe peritoneal cavity are completely avoided. Overdrainagewhich is the most frequent reason for shunt failure in con-ventional shunts is thus also avoided.l01520253035CA 02265859 l999-03- 11W0 98/ l 1934 PCT/DK97/003928Including a check valve such as a ball valve in the shuntwill hinder any reflux of blood from the sagittal sinus intothe shuntin such a way that it has substantially no resistance to the(or the ventricles). The check valve is constructedCSF flow through the shunt and has substantially no pressurethreshold to be overcome for the intracranial pressure. Thecheck valve which hinders retrograde flow of blood from thesagittal sinus can e.g. be constructed as a silicone ball ofthe same mass weight as CSF, which is placed in a chamberwhere the proximal, upstream inlet can be occluded by theball, and where the distal, downstream end is kept open byridges (6) around the orifice.According to a preferred embodiment, the check valve com-prises four guiding ridges (5) and four guiding and abutmentridges (6) in the chamber of the check valve. The ridges (5,6) extend parallel to the direction of flow of the liquid.The guide ridges (5) extend from the inlet side of the cham-ber of the check valve till approximately the middle of thechamber of the check valve where the guide and abutmentstart and extend to the outlet side of the cham-of thecheck valve from reaching the outlet opening of the chamberridges (6)ber. The ridges (6) serve to prevent the ball (4)of the check valve. The radial placing of the ridges (5, 6)can be directly recognized from Fig. 4.The use of the sagittal sinus as a permanent reception sitefor CSF inherits a risk of complicating thrombosis of thesagittal sinus. Placing a permanent drain in the sagittalsinus has previously been used in attempts to treat hydro-cephalus. A pressure regulating shunt system has been con-nected to a drain inserted in the sagittal sinus. The resultshave been reported in two papers, including in total 70(Hash et al. 1979; 1981). Thrombosis of thesinus was not seen in any of the reported cases. Hydrocephaâpatients Wen,lus could be treated by this method, but because of the useof a shunt type with inâbuilt, predefined opening pressure1015202530CA 02265859 l999-03- 11W0 98/1 1934 PCT/DK97/003929the shunts were only effective in cases with very highintracranial pressure.The flow of blood in the sagittal sinus has been measured atMRI studies. The very high flow in the range above 400 ml/mi-nute probably hinder formation of thrombus around the drainor in the sinus. As a part of the present project, the effectof placing a drain in the sagittal sinus was analyzed in ananimal investigation. In 5 dogs a silicone rubber catheterwas placed in the sinus and observed for more than 3 weeks.Examination of the drain, the walls of the sinus, and thesinus itself did not macroscopically or at histologicalexamination show any sign of thrombosis or endothelial proli-feration on the drain or in the sinus.In a preferred embodiment of the cerebrospinal fluid shuntsystem, the internal radius (R) of the tubular flow passagerestricting means is less than about 0.20 mm and the flow-restricting part of the tubular flow passage restrictingmeans has a length (L) which is calculated according to thelaw of Hagen-Poiseulle taking into consideration the aim toprovide a resistance to CSFâoutflow through the shunt whichis similar to the normal resistance, i.e. 8-12 mm Hg/ml/minIn particularly preferredof the tubular flowpassage restricting means is e.g. about 0.10 mm, aboutsuch as about 10 mm Hg/ml/min.embodiments, the internal radius (R)0.11 mm, about 0.12 mm, about 0.13 mm, about 0.14 mm, about0.15 mm, about 0.16 mm, about 0.17 mm,0.19 mm and the length (L) is calculated accordingly.about 0.18 mm or aboutAn as example, the length (L) can be calculated as follows:L=((ICP Pss)*w*R4)/8*F*V Hagen-Poiseulleâs lawwherein ICP is the intracranial pressure, PS5 is the pressurein the sagittal sinus, F is the flow rate of the cerebrospi-nal fluid and V is the viscosity of the cerebrospinal fluid.If ICP PS8 is set to be 4 mm Hg, R is set to be 0.15 mm, F1015202530CA 02265859 l999-03- llwo 93/1 1934 PCT/DK97/0039210is set to be 0.3 ml/min and V is set to be 0.0072 dyn*s/cmz,then for a Rout between 8 and 12 mm Hg/ml/min, the length iscalculated to be between 1.77 cm and 2.65 cm. In a similarmanner, the dimensions of various tubular flow passage re-It will be evident thatvarious combinations of dimensions as illustrated in Fig. 10stricting means can be calculated.are within the scope of the invention.In the laboratories of Danish Technological Institute (DTI)the dimensioning has been tested in a test bench. The resultsof the tests correspond to the calculated results for variousdimensions. This means that it is possible to construct ashunt system that has the same resistance to outflow of CSFas the normal, ânaturalâ CSF pathways possess. It should benoted that although the above formula can be used as a guid-ance, the results of the practical investigations have shownthat the relationship between the resistance to outflow ofCSF (Rout) and the length of the tubular flow passage re-stricting means is not completely linear. For practical pur-poses, however, Hagen-Poiseulleâs law can be used to calcu-late appropriate dimensions of the tubular flow passagerestricting means.In general, the tubular flow passage restricting means willhave a length within the range of 3.5 mm to 83.8 mm, prefer-ably within the range of 17.7 mm to 26.5 mm, such as about22.1 mm,body. This length may be divided in two or more individualeither in itself or defined within said shunt mainsegments, if considered appropriate, as illustrated in Figs.2 and 3.BEST MODE FOR CARRYING OUT THE INVENTIONIn a presently preferred embodiment, the shunt consists of acatheter for the ventricle, a body (Figs. 1 to 6) containingthe resistance device and a ball valve substantially withoutany inherited resistance compared to the resistance in the10202530CA 02265859 l999-03- llwo 93/1 1934 PCTIDK97/00392llflow passage restricting means, and a drain to be introducedinto the sagittal sinus.The shunt is placed subcutaneously on the top of the calva-rium, behind the coronal suture on the right (or left) sideof the sagittal suture. Via a burrhole a catheter is insertedin the right (or left) ventricle and connected to the body ofthe shunt. A small burrhole (2-3 mm) is placed directly overthe sagittal sinus, running in the midline beneath the readi-ly identifiable sagittal suture. A drain of the same outerdiameter as the burrhole is introduced into the sagittalâdistalâ end of the shunt.and 9 show the principles of the location of the shuntsinus and connected to the Figs. 8device.Suitable ventricular drains are well-known within the art andcan e.g. be a plain, 3 mm outer diameter silicone rubberdrain. Standard produced drains may be preferred.In a presently preferred embodiment, the shunt main body isconstructed from a suitable material such as a siliconerubber and has preferably an antechamber with a perforabledome. In the proximal (âthe topâ) end the dome ends in a tipwhere the ventricular drain can be connected and secured. Inthe distal end of the dome the inlet to the flow regulator isplaced.The antechamber will generally have a flat bottom consistingof hard silicone rubber. The dome is made of soft, per-forable, self-healing silicone rubber. The ventricular drainis attached to the inlet connector, which is provided with abrim. The length of the connector is generally about 5 mm.The drain is secured the usual way e.g. by a ligature. Theantechamber is attached to the tubule containing the tubularflow passage restricting means.The tubular flow passage restricting means is dimensionedaccording to Hagen-Poiseu1le's law to a resistance to flow at101520253035CA 02265859 l999-03- llwo 98/11934 PCTIDK97/0039212about 8-12 mm Hg/ml/min such as 10 mm Hg/ml/min. In a pre-sently preferred embodiment the tubular flow passage restric-ting means has a length of about 22.1 mm which may be divided2 and 3)the flow-restricting part of the device is 0.15 mm. The tubu-into two parts (see Figs. and the internal radius oflar flow passage restricting means is substantially straightand the walls are substantially smooth. The material of thetubular flow passage restricting means can be hard siliconerubber or HD polyethylene (e.g. gas sterilized polypropy-lene), polysulfone,polycarbonate, polystyrene or PVC. Alter-natively, the tube can be of titanium.The valve means may consist of a chamber into which the flow1-3 and 5-7). A ballmade of a material with the same mass weight as CSF is placedregulating tube ends in a bowl (Figs.in the chamber. Examples of such material are polyethylene,polysulfone, polystyrene and glass with air inside. Thedistal end of the chamber leads to the tubule where the drainfor the sagittal sinus is to be attached.three ridges stop the ball from occluding the flow in theIn one embodiment,direction of the sagittal sinus. Figs. 2-4 show an alterna-tive embodiment wherein the housing is circular or oval anddesigned so that the ball is only supported by two ridges ata time, said ridges having sharp contours in order to avoid"adhesion".Alternatively, the check valve could be placed at the inletend of the flow regulating tube. As an example, the valvemeans may consist of said ball embodied in a chamber endingat the inlet end of the tube in sharp ridges. The openinginto the antechamber may be circular, the edges of the holerigid, and the diameter of the hole smaller than the ball(Figs. 5-7).The valve mechanism may be constructed with a flat back side(see Fig. 2). The outlet of the first flow-regulating tubemay be provided with soft lips or have an excavation matchingthe periphery of the ball.10152052530CA 02265859 l999-03- 11W0 98/1 1934 PCT/DK97/0039213Alternatively, the check valve means could be with guidedrigid valve members, e.g. shaped as rings, or be with flex-ible valve members e.g. with tongueâshaped laminae.The drain for the sagittal sinus may be made of e.g. titaniumtube or silicone rubber tube. The distal 5 mm of the tubewill generally have an outer diameter of 2 mm and an innerdiameter of 1.5 mm. The part of the drain that goes throughthe skull has generally an outer diameter of 3 mm, the innerdiameter is 1.5 mm. The part of the drain with the largestdiameter may be shortened to fit the distance from the bodyof the shunt to the hole over the sagittal sinus.Another design of the drain is to use a titanium tube with aninner diameter of 1.5 mm and a length of 20 mm. The tube isattached to a silicone rubber tube with outer/inner diameter3/1.5 mm and of 60 mm length. The titanium tube is readilyinserted via a 2 mm wide burrhole through the bone coveringthe sagittal sinus. A stilet in the tube allows the insertedtube to be angled somewhat to lead the silicone rubber tubefollowing the surface of the skull to the body of the shunt.REFERENCESâ EP 066 685â US 4,605,395â US 4,781,673- US 4,904,236â Aschoff A, Kremer P, Benesch C, Fruh K, Klank A, Kunze S.Overdrainage and shunt technology. A critical comparisonof programmable, hydrostatic and variableâresistancevalves and flowâreducing devices. Child's Nerv. Syst.1995; ll:l93â202â Bergesen SE, Gjerris F. The predictive value of conduc-tance to outflow of CSF in normal hydrocephalus. Brainl982;lO5:65-861015202530CA 02265859 l999-03- 11WO 98111934 PCT/DK97/0039214- Borgesen SE, Gjerris F. The relationships between intra-cranial pressure, ventricular size and resistance to CSFoutflow. J Neurosurg 1987;67:535-39- Borgesen SE, Gjerris F, Schmidt J. Measurement of resi-stance to CSF outflow by subarachnoid perfusion. In:Gjerris F, Bzrgesen SE, Sorensen PS, eds. Outflow ofcerebrospinal fluid. Copenhagen: Munksgaard, 1989, pp121-29.- Borgesen SE, Gjerris F, Fedderss O, et al.:of resistance to outflow. Clinical experiences in 333In Hoff I, Betz AL (eds.):sure VII, Berlin, Springer Verlag: 353-355,Measurementpatients. Intracranial pres-1987.- Drake JM, SainteâRose C The Shunt Book, pp 146, BlackwellScience 1995.- Hash CJ, Shenkin HA,Crowder LE ventricle to sagittalsinus shunt for hydrocephalus. Neurosurgery l979;4: 394-400.â Wen HL Ventriculoâsuperior sagittal sinus shunt forhydrocephalus. Surg. Neurol. 1982;17: 432-434.Legends to figures of flow regulator and valve mechanismConnector tube for ventricular drain.Antechamber,Flow regulating tubes,compressible and perforable dome.dimensioned to a constant resis-tance to flow, may be divided in two parts by a valvemechanism.4. Ball, polyethylene, mass weight equal to cerebrospinalfluid.5. Ridges controlling movement of ball, distance betweenthe edges equals diameter of ball. Ball is pressedupstream when flow is inverted and prevents flow whenpressed against the outlet of the tube.6. Ridges controlling movement of ball at distal (down-stream) end of valve. Ridges narrowing to a lesserdiameter than ball, stopping the ball from closing the10W0 98/1 193410.ll.12.13.14.15.CA 02265859 l999-03- llPCTIDK97/003921 5inlet of the second part of the flow regulator when flowis from ventricles to sagittal sinus.Connector tube for sagittal sinus drain.Collar of connector tube.Check valve.Direction of flow.Dura mater.The skull.Shunt main body.ventricle catheter.Ventricle.Sinus sagittalis.