Cerebrospinal fluid purification system

Abstract

To provide a method and system for processing and removal of one or more target compounds from CSF of a patient.SOLUTION: The present invention provides methods and systems for conditioning cerebrospinal fluid (CSF). The methods provide efficient removal of target compounds from CSF. The systems provide a multilumen flow path and exchange of a majority volume portion of CSF in the CSF space. The removal and / or delivery of specific compounds can be tailored to the pathology of the specific disease. The removal is targeted and specific, for example, through the use of specific size-exclusion thresholds, antibodies against specific toxins, and other chromatographic techniques, as well as delivery and / or removal of targeted therapeutic agents. The invention finds use as a diagnostic, therapeutic and drug delivery platform for a variety of diseases affecting the CNS by accessing the CSF space.SELECTED DRAWING: Figure 8-1

Description

[Technical field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 60 / 828,745, filed October 9, 2006. The entire disclosure of U.S. Provisional Patent Application No. 60 / 828,745 is incorporated herein by reference for all purposes.

[0002] The present invention relates generally to medical devices and methods. More specifically, the present invention relates to devices, systems, methods and kits for removing toxins from cerebrospinal fluid (CSF). More specifically, the methods and systems can be used to diagnose and treat disorders affecting the central nervous system (CNS) by measuring and modifying the chemical composition of CSF. [Background technology]

[0003] Devices for the handling and / or removal of cerebrospinal fluid (CSF) to and from a patient have been described by others.

[0004] For example, several patents disclose various methods for diverting or diverting CSF from the CSF space (ventricles, spinal column) to another part of the body (e.g., abdomen, peritoneal cavity). See, for example, US Pat. Nos. 2,969,066; 3,889,687; 6,575,928 and 7,118,549. Other patents describe administration of therapeutic agents to the CSF space, but do not disclose removal of CSF. See, for example, US Pat. Nos. 5,531,673; 6,056,725; 6,594,880; 6,682,508 and 6,689,756. In general, therapeutic agents are delivered locally to the brain, but not to the larger cerebrospinal fluid space, including the brain and spine. Other patents disclose removal of CSF, but generally do not administer therapeutic agents and any other fluids. See, for example, U.S. Patent Nos. 3,889,687; 5,683,357; 5,405,316 and 7,252,659.

[0005] Although devices exist that have both infusion and drainage catheters for administering therapeutic agents or synthetic CSF and removing endogenous CSF, the close spatial arrangement of the inflow and outflow catheters does not result in CSF flow throughout the cerebrospinal fluid space or total CSF exchange that provides access to the entire volume of CSF within the cranial and spinal cord. See, e.g., U.S. Patent Nos. 4,378,797; 4,904,237; 6,537,241 and 6,709,426.

[0006] Furthermore, publications disclosing CSF replacement describe the replacement of endogenous CSF with synthetic CSF replacement fluids. See, for example, U.S. Patent No. 5,399,623; and U.S. Patent No. 5,433,636 and U.S. Patent No. 5,433,636. In this way, the concentration of toxic species can be diluted but not removed. It has been proposed to remove the debris and then implant a ventriculoperitoneal shunt system to treat drug overdoses or to remove tumor cells. Such devices are unnatural in that they do not remove the toxins of interest from the patient's endogenous CSF, but rather require flushing the entire system with an artificially generated solution, require liters of replacement fluid to be injected and delivered periodically, do not target or focus on the removal of specific toxins of interest, and are only practical in acute situations where liters of fluid can be injected. See, for example, U.S. Patent No. 5,433,623.

[0007] Although various devices exist that seek to access the CSF or indirectly target the nervous system, no CSF ​​purification system exists that allows for the direct, targeted, logical and disease-specific removal of one or more target compounds or the use of dual or multi-lumen catheters to affect or control the flow, mixing and turnover efficiency of the CSF.

[0008] It would be desirable to provide a method and system for processing and removing one or more target compounds from a patient's CSF. Recently, a modified ventriculoperitoneal shunt system has been used to propose a treatment for Alzheimer's disease that utilizes the removal of CSF by diverting fluid from the brain (ventricular system) to another part of the patient's body (e.g., abdominal / peritoneal cavity). See, for example, U.S. Patent No. 5,339,633 and U.S. Patent No. 5,339,633. The rationale is that by continuously draining CSF at a low rate, forcing the body to produce new CSF every day, the concentration of contaminants remaining in the endogenous CSF is diluted. Such systems have several inherent limitations. The rate at which the concentration of toxic species is reduced is mediated by passive flow, which is very slow, only a small portion of the total volume of CSF (a few milliliters) is addressed per hour, it does not target or focus on the specific items of interest, and it does not prevent the reabsorption of toxic species back into the systemic circulation, which would result in the toxic species returning to the CSF. See, for example, U.S. Patent No. 5,339,633; U.S. Patent No. 5,339,633; U.S. Patent No. 5,339,633.

[0009] The present invention addresses these and other needs. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] US Patent Application Publication No. 2003 / 0065309 [Patent Document 2] International Publication No. 01 / 154766 Brochure [Patent Document 3] International Publication No. 03 / 015710 Brochure [Patent Document 4] International Publication No. 01 / 54766 Brochure [Patent Document 5] U.S. Patent No. 5,980,480 [Patent Document 6] U.S. Patent No. 7,025,742 [Patent Document 7] U.S. Patent No. 5,980,480 [Patent Document 8] U.S. Patent No. 6,264,625 [Patent Document 9] U.S. Patent No. 6,689,085 Summary of the Invention [Means for solving the problem]

[0011] The present invention provides systems and methods for conditioning cerebrospinal fluid (CSF).

[0012] Thus, in a first aspect, the present invention provides methods for conditioning cerebrospinal fluid (CSF) in a patient. In some embodiments, these methods include: a) removing CSF from a first location in the CSF space of the patient; b) conditioning the removed CSF; and c) returning the conditioned CSF to the patient at a second location in the CSF space, wherein the removing and returning steps are performed simultaneously during at least a portion of the conditioning procedure.

[0013] In another aspect, the present invention provides methods for conditioning cerebrospinal fluid (CSF) in a patient, these methods comprising: a) introducing a catheter device into the CSF space of the patient's spinal cord through an access site in the spinal cord (e.g., sacral, lumbar, thoracic, cervical); b) advancing the catheter device through the CSF space of the spinal cord and into the skull (towards the brain) such that a distal port and a proximal port on the catheter device are positioned within the CSF space and spaced a preselected distance apart; c) withdrawing CSF through one of said ports; d) conditioning the collected CSF; e) returning the conditioned CSF through the other of said ports. Includes.

[0014] In another aspect, the present invention provides methods for conditioning cerebrospinal fluid (CSF) in a patient, these methods comprising: a) introducing a catheter device into the intraventricular or subarachnoid space of a patient; b) advancing the catheter device into the CSF space of the spinal cord such that a distal port and a proximal port on the catheter device are positioned within the CSF space and spaced a preselected distance apart; c) withdrawing CSF through one of said ports; d) conditioning the collected CSF; e) returning the conditioned CSF through the other of said ports. Includes.

[0015] In another aspect, the present invention provides methods for conditioning cerebrospinal fluid in a patient, these methods comprising: a) introducing a catheter device into a ventricle of a patient; b) adjusting the spacing between a pair of ports on the catheter device so that one port is located on one side of the ventricle and the other port is located on another side of the ventricle; c) withdrawing CSF through one of said ports; d) conditioning the collected CSF; e) returning the conditioned CSF to the ventricle through the other of said ports. Includes.

[0016] With respect to these method embodiments, in some embodiments, CSF is removed or withdrawn and returned at substantially the same flow rate. In some embodiments, CSF is removed or withdrawn and returned at the same flow rate. In some embodiments, the flow rate ranges from about 0.04 ml / min to about 30 ml / min, e.g., from about 5 ml / min to about 20 ml / min, e.g., about 1, 2, 3, 5, 7, 10, 12, 15, 18, or 20 ml / min.

[0017] In some embodiments, the volume of CSF removed is less than the volume that would cause spinal headaches or symptoms of overdrainage, hi some embodiments, the volume of CSF removed from the patient is never more than about 35-45 ml, e.g., about 40 ml, 35 ml, 30 ml, or 25 ml.

[0018] In some embodiments, the distance between the first location and the second location is at least about 4 cm, e.g., about 5, 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, or 100 cm. In some embodiments, the distance between the first location and the second location is at least about two vertebrae apart.

[0019] In some embodiments, the first location or proximal port is at or above the sacral S1 or lumbar L5, and the second location is at or above the lumbar L3. In some embodiments, the first location or proximal port is at or above S1, L5, L4, L3, L2, L1, or above. In some embodiments, the second location or distal port is in the CSF space of the sacral, lumbar, thoracic, or cervical spine. In some embodiments, the second location or distal port is in one or more ventricles. In some embodiments, the second location or distal port is in the subarachnoid space of the skull.

[0020] In some embodiments, the first location or proximal port is in the subarachnoid space of the skull. In some embodiments, the first location or proximal port is in one or more ventricles. In some embodiments, the second location or distal port is in the CSF space of the lumbar, thoracic or cervical spine. In some embodiments, the second location or distal port is in the CSF space of the lumbar spine, for example, S1, L5, L4, L3, L2, L1 or above.

[0021] In some embodiments, the first location or proximal port and the second location or distal port are in the ventricular space.For example, the first location or proximal port and the second location or distal port can both be on opposite sides of one ventricle.In another example, the first location or proximal port is in the first ventricle, and the second location or distal port is in the second ventricle.

[0022] In some embodiments, the distance between a first location or proximal port and a second location or distal port is adjustable, for example, a pair of tubular members in a multi-lumen catheter can be axially adjusted relative to one another.

[0023] In some embodiments, the flow direction for removing or withdrawing CSF and the flow direction for returning CSF are periodically reversed so that during a portion of the procedure, CSF is returned to a first location and removed from a second location, for example, the flow reversal is a pulse to clear debris from the removal or return ports.

[0024] In some embodiments, the methods further include mixing the conditioned CSF with unconditioned CSF upon return of the conditioned CSF to the CSF space. In some embodiments, the methods include inducing turbulence upon return of the conditioned CSF to enhance mixing. For example, turbulence can be created by introducing one or more helical channels, textured (e.g., ribbed or knobby) channels, T-shaped separation channels, bellows, balloons, vanes, and / or multi-lumen catheters that include multiple outlets (e.g., side holes or ports). Turbulence can also be induced by high pressure injection (i.e., "jet") or directed outflow.

[0025] In some embodiments, conditioning includes removing target molecules (e.g., proteins, peptides, oligopeptides) from the CSF. For example, conditioning can include one or more separation steps selected from the group consisting of biospecific affinity (e.g., antibodies, nucleic acids, receptors, enzymes), immunoaffinity, cation exchange, anion exchange, hydrophobicity, and various size exclusion thresholds.

[0026] In some embodiments, the methods further comprise isolating the target molecule.

[0027] In some embodiments, conditioning involves removing pathological cells (eg, B cells, T cells, macrophages, red blood cells and other blood cells) and cellular debris.

[0028] In some embodiments, the conditioning step is performed external to the patient's body. In some embodiments, the conditioning step is performed using a conditioning unit implanted within the patient's body.

[0029] In some embodiments, the catheter device consists essentially of a single catheter body having a lumen connected to a distal port and another lumen connected to a proximal port.

[0030] In some embodiments, the methods include alleviating symptoms of Alzheimer's disease in a patient by removing at least one of beta-amyloid protein or tau protein from the CSF using the methods and systems described above and herein.

[0031] In some embodiments, the methods include alleviating symptoms of Parkinson's disease in a patient by removing at least one alpha-synuclein protein (including peptides or oligomers) from the CSF using the methods and systems described above and herein.

[0032] In some embodiments, the methods include utilizing the methods and systems described above and herein to alleviate symptoms of amyotrophic lateral sclerosis (ALS) in a patient by removing at least one of insoluble superoxide dismutase-1 (SOD1), glutamic acid, neurofilamentous proteins, and anti-GM1 ganglioside antibodies from the CSF.

[0033] In some embodiments, the methods include alleviating symptoms of cerebral vasospasm in a patient by removing at least one of blood cells (e.g., red blood cells), oxyhemoglobin, and endothelin from the CSF using the methods and systems described above and herein.

[0034] In some embodiments, the methods include alleviating symptoms of encephalitis in a patient by removing at least one of the causative bacterial or viral entities, tumor necrosis factor-alpha (TNFα) and IgG from the CSF using the methods and systems described above and herein.

[0035] In some embodiments, the methods include alleviating symptoms of Guillain-Barre syndrome (GBS) in a patient by removing cells and at least one of inflammatory mediators, including but not limited to, C5a, TNFα, IL2, IL-6, interferon-γ, IgG, and endotoxins from the CSF using the methods and systems described above and herein.

[0036] In some embodiments, the methods include utilizing the methods and systems described above and herein to alleviate symptoms of multiple sclerosis (MS) in a patient by removing at least one of T cells, B cells, anti-myelin antibodies, and inflammatory mediators, including but not limited to, TNFα, IL2, IL-6, and interferon-γ, from the CSF.

[0037] In some embodiments, these methods include utilizing the methods and systems described above and herein to alleviate stroke symptoms in a patient by removing inflammatory mediators, including but not limited to, endothelin, and enolase, and cooling the CSF (and thus the CNS).

[0038] In a related aspect, these methods provide a system for conditioning cerebrospinal fluid (CSF) in a patient. In some embodiments, these systems include: i) a catheter assembly having a first lumen with a distal port and a second lumen with a proximal port, said catheter adapted for introduction into the CSF space, said ports being axially spaced apart; ii) a pump connectable between the first lumen and the second lumen for inducing flow of CSF therebetween; iii) a conditioning component connectable between the first lumen and the second lumen for conditioning the flow of CSF therebetween; and Includes.

[0039] With regard to these system embodiments, in some embodiments the catheter assembly consists essentially of a single tubular member having a first lumen and a distal port, with a second lumen and a proximal port fixedly disposed therein.

[0040] In some embodiments, the catheter includes a first tubular member having a first lumen and a distal port therein, and a second tubular member having a second lumen and a proximal port therein.

[0041] In some embodiments, the first and second tubes can be axially translated relative to one another to adjust the distance between them.

[0042] In some embodiments, the pump has an adjustable flow rate between about 0.04 ml / min and about 30 ml / min, e.g., about 5 ml / min to about 20 ml / min, e.g., about 1, 2, 3, 5, 7, 10, 12, 15, 18, or 20 ml / min. In some embodiments, the pump comprises a peristaltic pump that is isolated from the CSF flow. In some embodiments, the pump is implantable (e.g., an Archimedes pump).

[0043] In some embodiments, the conditioning component is selected from the group consisting of biospecific affinity, immunoaffinity, cation exchange, anion exchange, hydrophobicity, and size exclusion. For example, the conditioning component can be a column or cartridge. In some embodiments, the catheter comprises a conditioning component (e.g., covalently or non-covalently bound to the inner surface of the catheter).

[0044] For size exclusion and filtration, the filtration components can be of any type, for example, membranes, nanoparticles, flat surfaces, tubes or capillaries.

[0045] In some embodiments, the system has a CSF holding volume of less than about 40 ml, eg, less than about 35, 30, 25, or 20 ml.

[0046] In some embodiments the system is implantable, hi some embodiments the system is partially external. definition The term "patient" refers to any mammal. The mammal may be a non-human mammal, a non-human primate, or a human. In some embodiments, the mammal is a domestic animal (e.g., dog, cat, rodent, etc.), an agricultural mammal (e.g., cow, sheep, horse, pig), or a laboratory animal (rodent, rat, mouse, lagomorph, hamster).

[0047] The term "CSF space" refers to any volume of cerebrospinal fluid found in the cranial or spinal regions that is in contact with any component of the nervous system but not inside the tissues. Interstitial fluid is found in tissues.

[0048] The phrases "conditioning CSF" or "conditioned CSF" refer interchangeably to CSF ​​that has been partially, substantially, or completely removed of one or more target compounds.

[0049] The phrase "consisting essentially of" refers to elements recited in a claim and to intangible elements, excluding elements that materially change the invention. The present invention also provides the following: (Item 1) 1. A method for conditioning cerebrospinal fluid (CSF) in a patient, comprising: removing CSF from a first location in the CSF space of the patient; conditioning the removed CSF; returning the conditioned CSF to the patient at a second location in the CSF space. wherein the removing and returning steps are performed simultaneously during at least a portion of the conditioning procedure. (Item 2) 2. The method of claim 1, wherein the CSF is removed and returned at substantially the same flow rate. (Item 3) 3. The method according to claim 2, wherein the flow rate ranges from 0.04 ml / min to 30 ml / min. (Item 4) 4. The method of claim 3, wherein the volume of CSF removed from the patient never exceeds 40 ml. (Item 5) 2. The method of claim 1, wherein the distance between the first location and the second location is at least 4 cm. (Item 6) 6. The method of claim 5, wherein the first location is at or above S1 and the second location is at or above L3. (Item 7) 7. The method of claim 6, wherein the second location is in the CSF space of the cervical spine. (Item 8) 7. The method of claim 6, wherein the second location is in a ventricle. (Item 9) 2. The method of claim 1, wherein the direction of flow removing and returning CSF is periodically reversed such that during a portion of the treatment, CSF is returned to the first location and removed from the second location. (Item 10) 10. The method of claim 9, wherein the flow reversal is a pulse to dislodge debris from a removal or return port. (Item 11) 2. The method of claim 1, further comprising the step of mixing the conditioned CSF with endogenous CSF upon returning the conditioned CSF to the CSF space. (Item 12) 12. The method of claim 11, wherein the mixing step includes inducing turbulence in returning the conditioned CSF. (Item 13) 2. The method of claim 1, wherein the conditioning step comprises removing the target molecule. (Item 14) 14. The method of claim 13, further comprising isolating the target molecule. (Item 15) 2. The method of claim 1, wherein the conditioning step comprises one or more separation steps selected from the group consisting of biospecific affinity, immunoaffinity, cation exchange, anion exchange, hydrophobicity and size exclusion. (Item 16) Item 17. The method of item 1, wherein the conditioning step is performed external to the patient's body. 2. The method of claim 1, wherein the conditioning step is performed using a conditioning unit implanted within the patient's body. (Item 18) 1. A method for conditioning cerebrospinal fluid (CSF) in a patient, comprising: introducing a catheter device into the CSF space of the patient's spinal cord through a lumbar access site; advancing the catheter device through the CSF space of the spinal cord toward the brain such that distal and proximal ports on the catheter device are positioned within the CSF space and spaced a preselected distance apart; withdrawing CSF through one of the ports; conditioning the collected CSF; returning the conditioned CSF through the other port. The method includes: (Item 19) 20. The method of claim 18, wherein the distal port on the catheter is advanced to a location in the CSF space of the cervical spine. (Item 20) 20. The method of claim 18, wherein the distal port on the catheter is advanced to a location in the subarachnoid space of the skull. (Item 21) 20. The method of claim 18, wherein the distal port and the proximal port are spaced apart by a distance of at least 4 cm. (Item 22) 20. The method of claim 18, wherein the catheter device consists essentially of a single catheter body having a lumen connected to the distal port and another lumen connected to the proximal port. (Item 23) 20. The method of claim 18, wherein the CSF is returned under conditions that enhance mixing of the returned CSF with unconditioned CSF. (Item 24) 24. The method of claim 23, wherein the conditions that enhance mixing of the returned CSF include one or more conditions selected from the group consisting of directed outflow, high pressure injection, injection through multiple ports, spiral catheter, T-catheter, bellows, ribbed catheter, vanes, and balloons. (Item 25) 1. A method for conditioning cerebrospinal fluid in a patient, comprising: introducing a catheter device into a ventricle; adjusting the spacing between a pair of ports on the catheter device so that one port is located on one side of the ventricle and the other port is located on another side of the ventricle; withdrawing CSF through one of the ports; conditioning the collected CSF; returning the conditioned CSF to the ventricle through the other port. The method includes: (Item 26) 26. The method of claim 25, wherein the spacing between the pair of ports is at least 4 cm. (Item 27) 26. The method of item 25, wherein each port is in a different ventricle. (Item 28) 26. The method of item 25, wherein both ports are in the same ventricle. (Item 29) 26. The method of claim 25, wherein adjusting the spacing between the pair of ports comprises axially translating the pair of tubular members relative to one another. (Item 30) 1. A system for conditioning cerebrospinal fluid (CSF) of a patient, comprising: a catheter assembly having a first lumen with a distal port and a second lumen with a proximal port, the catheter adapted for introduction into the CSF space, the ports being axially spaced apart; a pump connectable between the first lumen and the second lumen for inducing flow of CSF therebetween; a conditioning component connectable between the first lumen and the second lumen for conditioning the flow of CSF therebetween; A system including: (Item 31) 31. The system of claim 30, wherein the catheter assembly consists essentially of a single tubular member having the first lumen and the distal port, and the second lumen and the proximal port fixedly disposed therein. (Item 32) Item 31. The system of item 30, wherein the catheter includes a first tubular member having the first lumen and the distal port therein, and a second tubular member having the second lumen and the proximal port therein. (Item 33) Item 33. The system of item 32, wherein the first and second tubes are axially translatable relative to one another to adjust the distance therebetween. (Item 34) 31. The system of claim 30, wherein the pump has an adjustable flow rate between 0.04 ml / min and 30 ml / min. (Item 35) 35. The system of claim 34, wherein the pump comprises a peristaltic pump that is isolated from the flow of CSF. (Item 36) 31. The system of claim 30, wherein the conditioning component is selected from the group consisting of biospecific affinity, immunoaffinity, cation exchange, anion exchange, hydrophobicity and size exclusion. (Item 37) 31. The system of item 30, having a CSF holding volume of less than 40 ml. (Item 38) 31. The system of item 30, which is implantable. (Item 39) 1. A method of alleviating a symptom of Alzheimer's disease in a patient, comprising: removing CSF from a first location in the CSF space of the patient; removing at least one of beta-amyloid protein or tau protein from the removed CSF, thereby conditioning the CSF; returning the conditioned CSF to the patient at a second location in the CSF space. wherein the removing and returning steps are performed simultaneously during at least a portion of the conditioning procedure. (Item 40) 1. A method of alleviating symptoms of Parkinson's disease in a patient, comprising: removing CSF from a first location in the CSF space of the patient; removing at least one of alpha-synuclein fibrils and oligomers from the removed CSF, thereby conditioning the CSF; returning the conditioned CSF to the patient at a second location in the CSF space. wherein the removing and returning steps are performed simultaneously during at least a portion of the conditioning procedure. (Item 41) 1. A method of alleviating symptoms of amyotrophic lateral sclerosis (ALS) in a patient, comprising: removing CSF from a first location in the CSF space of the patient; removing at least one of insoluble superoxide dismutase-1 (SOD1), glutamic acid, neurofilamentous proteins, and anti-GM1 ganglioside antibodies from the removed CSF, thereby conditioning the CSF; and returning the conditioned CSF to the patient at a second location in the CSF space, wherein the removing and returning steps are performed simultaneously during at least a portion of the conditioning procedure. (Item 42) 1. A method for alleviating a symptom of cerebral vasospasm in a patient, comprising: removing CSF from a first location in the CSF space of the patient; removing at least one of red blood cells, hemoglobin, oxyhemoglobin, and endothelin from the removed CSF, thereby conditioning the CSF; and returning the conditioned CSF to the patient at a second location in the CSF space, wherein the removing and returning steps are performed simultaneously during at least a portion of the conditioning procedure. (Item 43) 1. A method of alleviating symptoms of encephalitis in a patient, comprising: removing CSF from a first location in the CSF space of the patient; removing at least one of tumor necrosis factor-alpha (TNFα) and IgG from the removed CSF, thereby conditioning the CSF; and returning the conditioned CSF to the patient at a second location in the CSF space, wherein the removing and returning steps are performed simultaneously during at least a portion of the conditioning procedure. (Item 44) 1. A method of alleviating symptoms of Guillain-Barre Syndrome (GBS) in a patient, comprising: removing CSF from a first location in the CSF space of the patient; removing cells and at least one of an inflammatory mediator selected from the group consisting of C5a, TNFα, IL-2, IL-6, interferon-γ, IgG, and endotoxin from the removed CSF, thereby conditioning the CSF; and returning the conditioned CSF to the patient at a second location in the CSF space, wherein the removing and returning steps are performed simultaneously during at least a portion of the conditioning procedure. (Item 45) 1. A method of alleviating symptoms of multiple sclerosis (MS) in a patient, comprising: removing CSF from a first location in the CSF space of the patient; removing from the removed CSF at least one of T cells, B cells, anti-myelin antibodies, and inflammatory mediators selected from the group consisting of TNF-α, IL-2, IL-6, and interferon-γ, thereby conditioning the CSF; and returning the conditioned CSF to the patient at a second location in the CSF space, wherein the removing and returning steps are performed simultaneously during at least a portion of the conditioning procedure. (Item 46) 1. A method of alleviating symptoms of stroke in a patient, comprising: removing CSF from a first location in the CSF space of the patient; removing at least one of endothelin and enolase from the removed CSF, thereby conditioning the CSF; and returning the conditioned CSF to the patient at a second location in the CSF space, wherein the removing and returning steps are performed simultaneously during at least a portion of the conditioning procedure. (Item 47) 47. The method of claim 46, further comprising cooling the CSF. [Brief description of the drawings]

[0050] [Figure 1] FIG. 1 shows sagittal sections of the brain and spinal cord illustrating the location of the choroid plexus and the passive flow of CSF through the CNS. The inset shows the arachnoid granulations located along the major venous sinuses, which are the primary sites of CSF reabsorption. [Diagram 2] A) View of the ventricular system from the lateral surface, B) anterior surface, C) superior surface, and D) detailed ventricular structure. [Diagram 3] FIG. 1 shows a three-dimensional view of the anatomy of the ventricles. [Figure 4] FIG. 1 shows the blood-brain barrier and blood-CSF barrier: A) Fenestrated capillaries that allow water and solutes to pass, B) Brain capillaries with tight junctions between endothelial cells that form the blood-brain barrier; require cellular transport, C) Epithelial cells of the choroid plexus form the blood-CSF barrier, allowing water and solutes but requiring cellular transport, D) Arachnoid villi allow bulk unidirectional flow of CSF into the major venous sinuses. [Diagram 5]FIG. 1 illustrates the oligomer hypothesis of neurodegenerative diseases. A multi-step process is believed to underlie many different neurological conditions. Disease-specific proteins undergo specific biochemical modifications that predispose them to join together to form globular intermediates known as oligomers. These oligomers are believed to be toxic and can subsequently stack with each other to form protofibrils and fibrils. The fibrils may then be isolated within intracellular inclusions (e.g., tau tangles) or extracellular deposits (e.g., Aβ plaques) in the case of Alzheimer's disease. [Figure 6A] FIG. 1 is a schematic diagram showing the ventricular, spinal and ventriculo-spinal approaches to access the CSF space for efficient turnover of conditioned CSF. [Figure 6B] FIG. 1 illustrates one embodiment of the dual and single ventricular approach of the present invention. [Figure 6C] FIG. 1 illustrates one embodiment of the spinal approach of the present invention. [Figure 7] 1 is a schematic diagram showing a single lumen system that creates a local vortex (shadow) and provides minimal mixing or access to cranial CSF. [Figure 8-1] (FIG. 8A) Schematic diagram of a dual chamber system of the present invention. Multi-chamber systems create active and dynamic flow, resulting in efficient mixing that is not limited by pressure volume since inflow and outflow are relatively equal. This allows parallel processing of CSF with maximum turnover, providing access to the cranial and spinal spaces as well as all CSF volumes (shading indicates mixing). [Figure 8-2] (FIG. 8B) The dramatic difference in CSF clearance afforded by a multilumen system with inflow and outflow separated by a significant distance (line D) and adjacent (line C) compared to a single lumen system (line B) and diffusion-limited flow (line A). (FIG. 8C) The effect of catheter inflow / outflow distance on the reprocessing rate of conditioned CSF. [Figure 9]1A and 1B are cross-sectional views of sample dual or multi-lumen catheters for use in the CSF space. These are only two examples of the many embodiments that can be envisioned to achieve one of the ultimate objectives of the present invention, which is a method for providing efficient mixing and rotation of the CSF. [Figure 10] 10A-10B show catheters with helical outflow paths that cause additional mixing at various outflow points. FIG. 10A shows a single helical outflow path over the last length (l) of the catheter. A straight outflow lumen connects to the helical path. The catheter contains a straight inflow lumen at the center. FIG. 10B shows a double helical outflow path catheter with an inflow path at the center. [Figure 11] FIG. 11A illustrates a double helical outflow pathway at different points along the catheter. The catheter contains a single inflow pathway at its center. As described herein, the pathways can be reversed, for example, by a pump mechanism. Thus, a catheter with a single inflow pathway and multiple outflow pathways can become a single outflow pathway with multiple inflow pathways. FIG. 11B illustrates how the helical pathway changes direction as another means of creating directional flow. [Figure 12] FIG. 12A shows two catheters joined by a double loop. The loop is fixed to one catheter and slides over the other catheter so that the distance "d" between the two ends can be adjusted. In this case, the inflow catheter connects to the sliding portion of the loop. FIG. 12B shows a dual lumen catheter surrounded by a tight-fitting thin-walled cannula. The outflow lumen of the inner catheter has a side port so that pulling back the cannula exposes an additional side port or opening, thereby increasing the distance between the inflow and outflow. [Figure 13](FIG. 13A) A dual lumen catheter with addressable holes on one lumen. (FIG. 13B) A two catheter system creating a dual lumen catheter. As shown, an outflow catheter is created by the space between the inner and outer catheters. [Figure 14] Figure 14A shows a dual lumen catheter with overlapping side ports for use in subarachnoid ventricular access. Foramina surrounded by parenchyma are blocked by parenchyma. These include overlapping portions. Figure 14B shows a close-up of the distal end, showing one overlapping foramina on the left. Figure 14C shows a central section, showing overlapping foramina. [Figure 15] FIG. 15A shows the distal section. FIG. 15B shows a catheter incorporating multiple balloons. Inflow and outflow lumens are seen on either side of a proximal "T-section." A lumen for inflating the balloons is above the T-section. Three balloon inflation ports can be seen from above through the thin membrane that forms the balloons. FIG. 15C shows a cross section of the distal end with the inflow and balloon inflation lumens visible along with the inflation ports. [Figure 16] 1 shows an inflated balloon. The catheter can contain a single or multiple balloons. The balloons can be spherical or long. Long, thin balloons are well suited for the spinal space. The distance between the balloons can be of uniform length or of different lengths. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] 1. Introduction The present invention provides methods, devices and systems for removing, detecting, returning and delivering compounds from and / or to the cerebrospinal fluid (CSF) space of a patient. Removal and / or delivery of specific compounds can be tailored to specific disease pathologies. Removal is targeted and specific, for example, by the use of specific size exclusion thresholds, antibodies against specific toxins and other chromatographic techniques, as is targeted delivery and / or removal of therapeutic agents. By accessing the CSF space, the present invention finds use as a diagnostic, therapeutic and drug delivery platform for a variety of diseases affecting the CNS.

[0052] For the first time, the present invention provides a targeted and logical therapeutic platform for treating a variety of debilitating and often devastating neurological diseases for which there are currently limited and ineffective treatment options. Examples of disease states treatable by the present CSF processing systems and methods include, but are not limited to, cerebral vasospasm, Guillain-Barre syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, stroke, cancer affecting the brain or spinal cord, prion diseases, encephalitis of various causes, meningitis of various causes, diseases secondary to enzymatic or metabolic imbalances, biological weapons, and the like. For the first time, the present invention provides patients with a disruptive technology that addresses known etiology and effectively alleviates symptoms and modifies disease for a multitude of neurological conditions.

[0053] CSF: Cerebrospinal fluid (CSF) is produced primarily by the human CNS in the third and fourth ventricles outside the brain by a network of blood vessels called the choroid plexus (Figure 1). This normally clear, watery fluid maintains a gradient between it and the interstitial fluid of the nervous system. Water and soluble substances are freely exchangeable between the CSF and the nervous system. Thus, many neurotransmitters, peptides and other neurotropic substances can be found in the CSF. The functional role of many of these peptides is currently being investigated. The concentration of various neurotropic substances in the CSF is of great interest, since it indirectly indicates a situation that corresponds closely to the extracellular fluid in the immediate vicinity of neurons in the brain and spinal cord. Thus, the CSF fulfills two main functions: 1) by covering the brain and spinal cord, the CSF provides a protective function, providing buoyancy and preventing traction on blood vessels and nerves upon impact against the skull or spinal column; 2) perhaps even more importantly, the CSF contributes to the maintenance of a constant composition of the neuronal environment. See Blumenfeld, H. (2002) Neuroanatomy through Clinical Cases., p. 951.

[0054] Neuroanatomy / Flow: In healthy adults, CSF is produced at a rate of about 0.3 ml / min, 18 ml / hr, or about 432 ml / day. However, the total volume found in the ventricles and in the subarachnoid space is about 150 ml (Figure 2). Thus, the total volume of CSF turns over several times (about 3 times) each day. Fluid produced in the lateral ventricles flows through the interventricular foramen (foramen of Monro) into the third ventricle and then through the narrow aqueduct to the fourth ventricle (Figure 3). From there, CSF exits posterior (foramen of Magendie) or lateral (foramen of Luschka) in the midline (Figure 2). CSF then spreads over the entire surface of the brain and spinal cord, providing a constant balance of extracellular fluid throughout the CNS and to individual neurons. CSF drains by small protrusions called arachnoid granulations, which are particularly prominent along major venous drainage sites such as the superior sagittal sinus (Figure 1, inset). Fluid passes through the subarachnoid space into the venous sinuses due to hydrostatic gradients. Some CSF also drains through other routes, such as lymphatic vessels along the nerves of the skull and spinal cord. See Blumenfeld, H. (2002) Neuroanatomy through Clinical Cases., p. 951.

[0055] Barriers: In most organs, low molecular weight substances pass relatively easily through the capillary walls, and therefore their concentration in plasma is similar to that in the interstitial (extracellular) fluid. The composition of the interstitial fluid of the CNS differs from that of most other organs due to selective properties of the capillaries of the brain, known as the blood-brain barrier (BBB). This barrier consists of extensive tight junctions between endothelial cells, which prevent the passage of many substances from the peripheral plasma (Figure 4). Similar to the BBB, the epithelium of the choroid plexus represents an additional barrier between the blood and the CSF, known as the blood-CSF barrier. Thus, many substances that can exit the capillaries of the choroid plexus cannot enter the CSF. The normal function of nerve cells depends on the precise control of ions and compounds in their extracellular environment. See Blumenfeld, H. (2002) Neuroanatomy through Clinical Cases., p. 951.

[0056] Neurological Diseases: Diseases affecting the nervous system are among the most devastating and debilitating medical conditions. There is an increasing understanding of the pathophysiology of the diverse endogenous and exogenous pathogens that can be found in the CSF, which directly or indirectly have deleterious effects on the CNS. This presents opportunities for intervention in disease processes and their prevention or mitigation. Furthermore, the system can be adapted to individual disease processes in a targeted and logical manner.

[0057] The notion that numerous distinct disorders of the brain and spinal cord require distinct disease-specific therapeutic interventions is being challenged by the discovery that some of the disorders share common underlying disease mechanisms. This provides an opportunity for intervention with a device platform that addresses a number of different diseases based on a few fundamental concepts. This platform involves the purification and modification of CSF based on size, biological components, and temperature.

[0058] It is now understood that a number of "endogenous pathogens" (neurotoxic molecules released into the CSF from the brain) as well as "exogenous pathogens" (cells and neurotoxic molecules from the peripheral circulation that enter the CSF) can perturb the normal environment of the CNS and are believed to play a major role in many diseases affecting the nervous system. See Caughey, B. and PT Lansbury (2003) Annu Rev Neurosci 26:267-98.

[0059] Many neurodegenerative disorders are characterized by aggregates of fibrillar proteins and neurotoxic oligomeric species that are associated with progressive brain degeneration and infiltration of pathological inflammatory cell types (e.g., B cells, T cells, macrophages). Caughey, B. and PT Lansbury (2003) Annu Rev Neurosci 26:267-98; and Taylor, JP, J. Hardy et al. (2002) Science 296(5575):1991-5. See Table 1 and Figure 5. Despite differences in the molecular composition of these fibrillar proteins and the brain regions and cell types affected in each disorder, these diseases share similar pathological mechanisms and therefore, from a medical device standpoint, they share similar therapeutic mechanisms.

[0060] [Table 1] Immunotherapy: Recently, immunological concepts in the treatment of conformational diseases have received more attention, and immunization approaches are being pursued to stimulate the clearance of brain beta-amyloid protein (Aβ) plaques, for example, in Alzheimer's disease (AD). These approaches include both active and passive immunization techniques. Active immunization approaches utilize different routes of administration, types of adjuvants, the use of modified Aβ epitopes and / or immunogenic Aβ conjugates. See Morgan, D., DM Diamond et al. (2000) Nature 408(6815):982-5. Passive immunization approaches include monoclonal antibodies or specific antibody fragments (Fab) directed against specific Aβ epitopes. See Monsonego, A. and HL Weiner (2003) Science 302(5646):834-8. Clearance of plaques as a result of immunotherapy may depend on multiple mechanisms. One theory involves direct interaction of antibodies or Fab fragments with the deposits, resulting in disaggregation and microglial cell-mediated clearance. A second theory involves antibodies acting as a sink for Aβ peptides, removing them from the CNS and preventing plaque deposition in the brain by passive redistribution along a concentration gradient of soluble Aβ oligomers between the brain, CSF and plasma. See Roberson, ED and L. Mucke (2006) Science 314(5800):781-4. There is significant data from animal studies in which substantial reductions in Aβ burden in transgenic mouse models were accompanied by improvements in memory impairment, supporting both mechanisms. See Janus, C., J. Pearson et al. (2000) Nature 408(6815):979-82. Promising evidence from Aβ immunization in transgenic mice, which showed clearance of Aβ plaques and amelioration of cognitive impairment, led to human clinical trials. Unfortunately, human patients actively immunized with Aβ immunogens have developed symptoms of meningoencephalitis as a result of active immunotherapy.Orgogozo, JM, S. Gilman et al. (2003) Neurology 61(1):46-54; Bayer, AJ, R. See Bullock et al. (2005) Neurology 64(1):94-101; and Gilman, S., M. Koller et al. (2005) Neurology 64(9):1553-62. Human patients passively immunized with antibodies against Aβ protein may develop endogenous neutralizing antibodies against the anti-Aβ antibodies, reversing the therapeutic effect of passive immunotherapy and potentially resulting in a deleterious increase in Aβ protein. See Hock, C., U. Konietzko et al. (2003) Neuron 38(4):547-54; Nicoll, JA, E. Barton et al. (2006) J Neuropathol Exp Neurol 65(11):1040-8; and Melnikova, I. (2007) Nat Rev Drug Discov 6(5):341-2.

[0061] The first concern with both active and passive immunization is the proinflammatory outcome after immunization, which may lead to microglial hyperactivation. In addition to the multiple inflammatory pathways believed to be involved in AD, there are also certain inflammatory pathways that are specifically activated after microglial stimulation, including the release of proteases and cytokines, as well as activation of oxidative burst during the process of Aβ clearance that may exacerbate brain inflammation and neurodegeneration associated with AD. In addition to inflammation, there are also concerns about the production of autoantibodies along with immune tolerance and the inability to reverse treatment once administered. Furthermore, the redistribution of soluble Aβ oligomers along the concentration gradient of the brain, CSF, and plasma is unclear, whether Aβ is degraded in plasma or taken up by specific organs. To address these concerns, therapies are needed that block antibodies from entering the CNS while also capturing the targeted toxic protein.

[0062] The CSF purification system described in this invention serves as a broad platform technology for the treatment of numerous diseases affecting the nervous system. Several examples are provided below, along with detailed rationales, for numerous neurological diseases for which there are currently limited or ineffective therapies.

[0063] It would be desirable to provide improved and alternative methods, systems, kits for the processing, purification, and / or modification of CSF for a variety of purposes. The current invention has numerous benefits and advantages over previously described methods. First, size-based removal of agents (red blood cells and their breakdown products in cerebral vasospasm, T and B cells in MS, autoantibodies in GBS, etc.). Recent advances in nanotechnology and ultrafiltration now allow removal of agents on the nanometer scale instead of micrometers, which is nearly a thousand-fold improvement over previous systems in targeted filtration. Previous size-based filtration methods were limited to 0.2 micron filters, allowing most of the smaller toxic molecules to pass directly through the filter and back into the patient.

[0064] Secondly, due to recent advances in immunotherapy, the current invention applies ex-vivo immunotherapy targeting the removal from CSF of pathogenic molecules that directly affect the CNS. Antibodies provide an unprecedented level of specificity for molecules that are too small to be removed by today's size filters. As described above, the application of immunotherapy in vivo faces a number of significant complications, including encephalitis and death. For example, by immobilizing antibodies to an immunoaffinity column using the streptavidin-biotin system (the strongest chemical bond known), CSF can be processed on antibody cartridges to achieve capture of toxic oligomers and / or proteins without risk of systemic antibody delivery, encephalitis or death. The use of biological separations (including Abeta and tau proteins in AD, alpha-synuclein in PD, etc.) can be applied to benefit a number of diseases by altering the neuro-immune axis using a platform-based ex-vivo immunotherapy approach.

[0065] Thirdly, it has been shown that the regulation of temperature by mild, moderate or severe hypothermia has beneficial effects in terms of neuroprotection.Localized cooling of the CNS without systemic effects on the heart, liver or kidney can provide additional benefits to a number of diseases, including stroke, traumatic brain injury and spinal cord injury.This goal is achieved by the present invention described below. 2. System of the Present Invention The CSF purification system includes a multi-lumen catheter incorporating two or more lumens for efficient exchange of CSF from either the cranial and / or spinal CSF spaces. The system creates dynamic circulation and significant mixing within the cranial or spinal CSF spaces. The invention allows for the processing of large volumes of CSF in a short period of time while minimizing the impact on the inherent intracranial / spinal pressures and volumes.

[0066] Purification (or compound removal) schemes can be tailored to specific diseases or disease groups based on a number of features, including size, affinity, biochemical characteristics and / or temperature, but more specifically, can be based on diffusion, size exclusion, ex-vivo immunotherapy using immobilized antibodies or antibody fragments, hydrophobic / hydrophilic, anionic / cationic, high / low binding affinity, chelating, antibacterial, antiviral, anti-DNA / RNA / amino acid, enzyme, magnetic or nanoparticle based systems. The systems allow passive flow but also include active pumping mechanisms that create transient or continuous flow, so that inflow and outflow are relatively equal to each other. Additionally, a number of safety measures are included to ensure patient safety, including but not limited to pressure sensors, velocity detectors, bubble detectors, pH, temperature, osmotic balance, blood pressure, transmembrane pressure sensors. Pressure sensors are also available to continuously record / maintain / adjust intracranial and / or intraspinal pressure. Programmable control of the collection, production and overflow drainage valves are additional contemplated features. The system is adjustable for a wide range of biological parameters and flows. Alarm and automatic on / off settings are further included to provide signals for first aid and investigation of the system. A given volume of CSF is outside the patient's body at any one time, which is less than the amount that causes spinal headaches or symptoms related to excessive drainage.

[0067] Thus, the CSF purification / conditioning system provides for the design of bi-lumen / multi-lumen catheters. Flow studies have shown that bi-lumen or multi-lumen catheters with inflow and outflow separated by an appropriate distance are useful for creating and maintaining dynamic circulation and efficient mixing / exchange of CSF. Given the usual variations in patient anatomy, such distances may vary from individual to individual. Thus, a system that allows for variation in this distance in situ or prior to application (i.e., implantation) would provide further improvement in performance, as such a system could be applied across a population. The flow dynamics created with such a system are dramatically different from single lumen systems or systems with inflow and outflow points located closely in space (Figure 7). Dye studies clearly demonstrate that the present system, incorporating a catheter with a dual or multi-lumen design and spaced infusion and drainage, allows for more turnover of raw CSF per minute, or greater efficiency resulting in minimal mixing of raw and processed CSF, thereby accessing a significantly larger portion of the total volume of CSF in a shorter period of time (Figure 8A). The design of the present system has a dramatic effect on CSF physiology and flow. In the present dual-lumen system, the distance separating the inflow and outflow sites determines the maximum "column of CSF" that can be initially processed and removed (Figure 8B). Catheter systems with two or more lumens and multiple holes for inflow and outflow along the length of the catheter not only minimize clogging, but also provide a significant increase in turnover and access to the basal cisterns, ventricles, cranial and spinal subarachnoid CSF, compared to cases previously described anywhere in the literature. The greater efficiency of removal of the target compound results from the reduction in reprocessing of the same fluid (Figure 8C).

[0068] Simple single-lumen catheter systems only generate local swirl, with minimal mixing, and therefore recirculate much of the same previously processed CSF. Such single-lumen systems do not generate sufficient mixing to adequately withdraw or circulate fluid from the cranial CSF space bathing the brain. In vitro studies have shown that when using the present invention, the rate of mixing, amount of new CSF circulated per minute, and access provided by multiple rotations of the cranial and spinal CSF volume results in a CSF processing system that provides much more rapid, efficient, and feasible access to the entire CSF system compared to systems achievable when using single-lumen systems. The present invention provides the ability to perform flow removal and return in parallel, rather than sequentially. Additionally, multi-lumen catheters can also incorporate adjustable distances between the inflow and outflow regions, providing additional freedom to create CSF mixing and circulation (FIG. 12).

[0069] Parallel or continuous processing of removal and return streams using the multi-lumen system of the present invention offers several advantages over single-lumen systems that require sequential processing. First, parallel processing is more efficient and requires fewer steps than sequential processing. Multi-lumen systems that provide continuous parallel processing can also be conveniently automated and are more suitable for implantation. Continuous parallel processing systems can be designed to be closed, which requires less human or manual intervention and better control of sterility. Furthermore, continuous flow processing is not limited by volumetric limitations in terms of throughput; a wide range of flow rates and volume exchanges can also be achieved (FIG. 9). The only limitation is the dead space volume of the tubing, especially in the case of partial external systems.

[0070] The shape of the lumen is also a factor to consider. Studies have shown that simple circular lumens are more prone to clogging, requiring repeated flushing and / or catheter replacement. The dual / multi-lumen catheter systems described herein include multiple designs, including but not limited to combinations of circular, elliptical, square, etc., in various sizes and orientations to avoid catheter clogging. The combination of temporary and / or continuous flow helps maintain lumen patency and significantly reduces the risk of clogging associated with today's systems. Dual or multi-lumen systems also allow for rapid clearing of clogs by flow reversal and intermittent flow reversal by the pumping system. Dual-lumen systems also provide the added benefit of increasing the duration of a particular flow direction by moving clogging agents further away from the injection site.

[0071] The distal portion of the catheter can be constructed to promote maximum mixing and exchange between the returning CSF and unconditioned CSF when returning conditioned CSF. The mixing enhancing elements can be external or internal to the patient's body. One example is a helical or double helix design with or without bellows to create maximum disruption / turbulence of the passive CSF flow and more complete mixing and exchange of the endogenous CSF with the processed CSF (i.e., FIG. 10). Other examples include the use of jets or directing the outflow to create swirl or turbulence, thereby enhancing mixing (FIG. 11).

[0072] Catheters can contain a number of distal geometries to enhance CSF mixing and exchange. One example is a T-catheter waist design (i.e., Figures 13 and 15) where both inlet and outlet lumens are inserted as a single catheter and the distal lumen is collapsible or positioned using a release mechanism to maximize the distance between the inlet and outlet sites and provide maximum surface area contact with the CSF space. Another example is the addition of small wings, non-planar surfaces, ridged sections or small balloon systems anywhere along the length of the cranial or spinal catheter that further creates mixing and exchange between the intrinsic CSF and the processed CSF (i.e., Figures 15 and 16). Examples of catheter designs that promote flow turbulence and mixing are shown in Figures 10-16.

[0073] Part of the purification system can be incorporated into the catheter itself by constructing the purification system with a membrane that allows for passive filtration of the underlying CSF and / or equilibration with treated CSF.

[0074] In some embodiments, the catheter includes a radio-opaque marker for accurate localization and confirmation of the location of the tip of the catheter in the space of the cranial or spinal CSF. The radio-opaque marker can then be visualized using plain x-ray or computed tomography. A variety of other methods can be utilized to confirm the placement and placement of the correct catheter. This includes the use of an endoscope to directly visualize the placement of the cranial or spinal catheter. This method may be particularly useful in patients with small cranial ventricles that contain CSF or in patients with spinal stenosis or scoliosis. In these cases, lumbar access is difficult.

[0075] One of the major concerns with any implantable device is the risk of infection. The risk of infection of the CSF is significant and includes meningitis, encephalitis and even death. A number of safety measures can be incorporated into the present invention to minimize and / or eliminate the possible risk of infection for the patient. First, the proximal end of the catheter can be inserted at various distances away from the entry site to minimize the risk of organisms tracing back from the skin surface entry site. Second, the catheter access site can be meticulously cleaned daily by a nurse or the patient can be taught to do so. Third, antibiotics can be administered to the patient immediately prior to catheter placement, during the period the catheter is indwelling during processing of the CSF, and immediately after removal to further reduce the risk of infection. Fourth, the catheter system itself can be impregnated with the specific antibiotic of choice. Fifth, specific metals can be incorporated that can generate a temporarily charged surface. Such metals have generally been shown to inhibit bacterial ingrowth and the development of catheter infections. Sixth, an optional antibiotic can be delivered into the CSF at a specific time before, during or after CSF processing to further eliminate the risk of bacterial seeding or infection. Finally, an antibiotic cuff can be placed at one or more locations along the catheter system to further reduce any risk of infection.

[0076] Another concern with any catheter system is the risk of kinking or physical blockage. The current invention incorporates multiple safety sensors to ensure that inflow and outflow are generally relatively equal. However, the incorporation of a specific shape memory alloy into the catheter for use in the CSF space (e.g., in one of the lumens in FIG. 9B) can also be an additional strategy to prevent kinking, maintain shape, and allow maximum access to the CSF space. Nickel titanium is a shape memory alloy, also commonly referred to as Nitinol. Above its transformation temperature, it becomes superelastic and can withstand large amounts of deformation. Below its transformation temperature, it exhibits a shape memory effect. Once deformed, it will remain in that shape until it is heated above its transformation temperature, at which point it will return to its original shape. Nitinol is typically made up of about 55% nickel by weight, and slight changes in composition can significantly change the transition temperature of the alloy, making it suitable for many applications in medicine in this regard. In some embodiments, the catheter incorporates nickel titanium into its manufacture. Such catheters allow easy entry of the catheter through the cranial or spinal access pathways due to the superelasticity of Nitinol, while once in the CSF space, its shape memory allows it to return to its previous structure. The physical function of Nitinol is similar to biological muscle, contracting when activated. The contraction motion can be applied to any task requiring physical motion with low to moderate circulatory speed. Small motors or solenoids can also be replaced with Nitinol due to its small size, light weight, ease of use and quiet operation. Such catheter systems, which are internally adjustable and adapted to access various regions of the cranial or spinal CSF space, while minimizing the risk of kinking and catheter blockage, are additional features of the present invention.

[0077] In some embodiments, these systems incorporate conductive materials or heat exchange elements within a portion of the catheter system (e.g., within one of the lumens in FIG. 9B) that allow for rapid and direct changes in the CSF space in the case of injuries that require rapid adjustment of temperature. Although the neuroprotective effects of significant hypothermia have long been recognized, the use of hypothermia for the treatment of neurological injuries has often been abandoned due to problems with administration and severe side effects such as cardiac arrhythmias, chills, infections, and coagulation disorders. During the past decade, it has become recognized that mild (34° C. to 36° C.), moderate (34° C. to 28° C.) and severe (<28° C.) hypothermia allows for therapeutic thermoregulation and can substantially prevent ischemia-induced brain damage in both experimental stroke and other neuronal injuries. Following focal cerebral ischemia, hypothermia has been found to reduce infarct volume by up to 90% and has a significant beneficial effect on patients suffering from traumatic brain injury or spinal cord injury. In contrast, hyperthermia has been shown to have a profoundly negative effect on CNS histopathology and outcome.

[0078] Such temperature-adjustable cooling catheters designed specifically for the cranial or spinal CSF space can be used independently or in conjunction with previously described extracorporeal cooling systems to provide an additional mechanism for rapid and direct CNS cooling without the systemic side effects on the heart or clotting cascade seen with cooling the entire blood volume. Such CSF cooling systems have multiple applications, including but not limited to stroke, traumatic brain injury (TBI), and spinal cord injury (SCI), and can be used independently or in conjunction with various purification / conditioning schemes as described above and herein. In addition to systemic body temperature, endogenous CSF and processed CSF temperature sensors can be incorporated into the heating / cooling system to appropriately record / maintain / regulate temperature.

[0079] The system allows for the connection of multiple different CSF inflows and outflows for processing of CSF between any point in the CSF system so that the overall inflows and outflows are relatively equal. The spatial locations of the inflow and outflow ports are sufficiently separated to allow CSF to flow throughout the majority or entirety of the CSF space. Custom cranial or spinal catheters can be introduced through a number of routes, including but not limited to single ventricular insertion, dual ventricular insertion, single level spinal cord insertion, two / multiple levels spinal cord insertion, and ventriculo-spinal. In some embodiments, a first catheter is inserted into the ventricle or cervical spine and a second catheter is inserted into the lumbar spine. Additionally, any of the above systems may be constructed to exchange CSF from any two points within the subarachnoid space. One example is a ventricular catheter with an inlet / outlet site that communicates with the subarachnoid space covering the adjacent brain parenchyma.

[0080] The system allows for active movement of large volumes of CSF over long periods of time, without the need for removal or diversion of CSF from the human body. Various inlet and outlet sites in the custom-made catheter allow the system to generate active CSF flow in addition to the normal passive CSF flow. Active movement of CSF can be generated by a number of methods, including, but not limited to, electrically powered pumps for active CSF withdrawal and return. Additionally, the pump system may have a variety of mechanisms to facilitate the requirement of relatively equal inflow and outflow. Examples of suitable pumps include rotary pumps, syringe-powered pumps, positive displacement pumps, peristaltic pumps, piston pumps, air pumps, bellows, electromagnetic pumps, magnetostrictive pumps, hydraulic pumps, and others. The pump may be a single device with bidirectional capabilities, or two unidirectional pumps in communication with each other. There are several pumping mechanisms available to achieve the desired endpoint of generating active CSF flow in addition to the normal passive CSF flow. The pump may be external or internal to the patient's body. Internal or implantable pumps are known in the art (eg, the Archimedes pump).

[0081] In some embodiments, these systems provide a customizable conditioning system based on the specific disease to be addressed. Removal of specific compounds can be targeted based on size exclusion, specific antibodies, hydrophobic-hydrophilic interactions, anion-cation exchangers, compounds with high-low binding affinity, antibacterial, antiviral, anti-DNA / RNA, immunotherapy applications, immunomodulatory, enzymatic digestion, etc. In addition to various neurochemical filtration approaches, other filtration systems based on electromechanical principles may be utilized, including radio frequency, electromagnetic, sonic, piezoelectric, electrostatic, atomic force, and ultrasonic filtration. Other features can be added to the filtration system, including differential centrifugal forces to aid in the rapid separation of items of interest, such as ultrafiltration products, proteins, cells, etc.

[0082] In some embodiments, a cartridge-based scheme or a combination of the purification-based schemes described above can be used for rapid changeover. For example, a system combining size, antibody and charge-based approaches with single or multiple cartridges for purification is envisioned, so that when it is time to replace purification filters, antibodies, etc., replacement can be performed with an easy-to-use, rapid-change system. The conditioning system or chromatographic cartridges (e.g., biospecific interaction, ion exchanger, size exclusion) can be external or internal to the patient's body. In some embodiments, the conditioning cartridge or filter is contained within one or more lumens of a multi-lumen catheter. In some embodiments, the catheter lumens or sections thereof are coated (e.g., covalently or non-covalently) with chromatographic moieties (e.g., biospecific capture moieties including antibodies and nucleic acids, cation or anion exchangers, hydrophobic moieties, and others).

[0083] In some embodiments, these systems include sensors for intermittent or continuous monitoring and / or sampling of CSF levels of specific compounds or parameters of interest. For example, in the case of cerebral vasospasm, red blood cells, hemoglobin, endothelin or other molecules can be sampled continuously and their levels quantified to indicate the degree to which the system has cleared the CSF. Similarly, in the case of Alzheimer's disease, levels of Aβ, tau or other molecules can be measured to indicate the production or removal of specific items of interest. Sensors can be utilized to non-invasively record / maintain / adjust the levels of specific compounds in the CSF. 3.How to use A. Methods for conditioning cerebrospinal fluid The present invention provides a method for conditioning the cerebrospinal fluid of a patient using the system of the present invention. A cranial or spinal catheter is placed using appropriate anatomical landmarks known to those skilled in the art, thereby contacting the custom-made catheter with the CSF space of interest. A cranial catheter is placed at a specific point and trajectory to enter the CSF space of the ventricles or the subarachnoid space of the skull above the brain parenchyma. For a spinal catheter, a cannula is placed at any point along the spinal canal, often in the lumbar region, to provide a conduit for placing the custom-made spinal catheter into the CSF space. Specifically, a multi-lumen spinal catheter can be inserted between the lumbar vertebrae of a patient, for example, using a needle cannula to advance the catheter. In some embodiments, a sacral catheter is inserted into the sacral region above S1. In some embodiments, a lumbar catheter is inserted into the lumbar region above L5, L4, L3, L2, or L1. In other embodiments, a spinal catheter is inserted between the thoracic or cervical vertebrae. For both spinal and cranial entry, the patient may be in a supine, sitting position, or at any angle between 0° and 90°.

[0084] CSF is removed from the cranial or spinal CSF space, passed through a disease-specific conditioning system, and returned to another location in the cranial or spinal CSF space. CSF is removed using natural passive flow as well as a combination of augmentation of natural passive flow with a pumping mechanism that creates active CSF flow dynamics. The volume of CSF outside the body at a given time is less than the volume that produces spinal headache or symptoms of overdrainage (about 40 ml). The location of the catheter can vary, but can include central ventricular insertion, dual ventricular insertion, single level spinal cord insertion, two / multiple levels spinal cord insertion, and single, multi-lumen, or combination catheters placed by ventriculo-spinal.

[0085] One illustrative example is the use of a single level spinal insertion, with the catheter tip in the cervical region, inserted into the lumbar space, and pumped into the cranium. In this example, CSF inflow can be from the cervical region, and outflow can be from the lumbar region and / or anywhere along the length of the multi-lumen catheter, depending on the number and location of outlets along the outflow lumen. In another embodiment, inflow can be in the lumbar region, and outflow can be in the cervical, subarachnoid, or ventricular regions. In another embodiment, both inflow and outflow ports are in the cranial space, e.g., one port is in the first ventricle and the second port is in the second ventricle. In another embodiment, the inflow and outflow ports are located on different sides of the same ventricle.

[0086] The flow rate may vary and is limited by the pressure differential experienced by the walls of the catheter, but may generally range from 0.04 ml / min to 30 ml / min, for example from about 5 to 20 ml / min, e.g., about 0.5, 1, 2, 5, 8, 10, 12, 15, 20 ml / min.

[0087] The CSF is then conditioned using a variety of mechanisms, generally including size, biomolecular specificity and / or temperature mediated mechanisms, as described above. In carrying out the conditioning step, the removed or collected CSF is contacted with one or more substrates that contain a chromatographic, electrochemical or electromechanical selection agent.

[0088] These methods provide customizable conditioning schemes based on the specific disease process to be addressed and the target compounds to be removed from the CSF. Depending on the target compound or compounds to be removed (e.g., proteins, oligomeric peptides, amino acids, nucleic acids, bacteria, etc.), the CSF can be contacted with one or more substrates including size exclusion filtration, hydrophobic-hydrophilic interactions, anion-cation exchangers, compounds with high-low binding affinity, biospecific interactions including antibacterial, antiviral, nucleic acid hybridization and immunoaffinity (e.g., antibodies or non-antibody binding proteins), enzymatic digestion, or combinations thereof. The antibodies can be whole immunoglobulin molecules or fragments thereof (e.g., FAbs, single chain variable regions (scFvs), variable regions). Non-antibody binding molecules based, for example, on A-domain scaffolds also find use. In addition to various chromatographic approaches, electromechanical-based filtration systems also find use, including filtration using radio frequency, electromagnetic, sonic, piezoelectric, electrostatic, atomic force, and ultrasound. The CSF may also be subjected to differential centrifugal forces to aid in the rapid separation of items of interest, such as ultrafiltration products, proteins, cells, etc.

[0089] In some embodiments, the CSF is contacted with multiple substrates, e.g., a combination of size, biospecificity, and charge-based selection criteria. The conditioning step can be performed externally or internally to the patient's body. In some embodiments, the conditioning substrate is contained within one or more lumens of a multi-lumen catheter. In some embodiments, the catheter lumens or sections thereof are coated (e.g., covalently or non-covalently) with chromatographic moieties (e.g., biospecific capture moieties, including antibodies and nucleic acids, cation or anion exchangers, hydrophobic moieties, and others).

[0090] The concept of ex-vivo immunotherapy using CSF (i.e., immunoaffinity) is itself broadly applicable and is a novel component of the present invention. Numerous conditions affecting the nervous system are now better understood, and a common feature is the disruption of the neuroimmune axis or weak point in the blood-brain barrier, resulting in B-cell, T-cell, and humoral and cell-mediated immune responses. In both cases, normal neuronal structures are victimized by a wide range of neuroinflammatory components and reactive oxidative stress proteins. The present invention allows targeted removal of inflammatory cells and proteins and elimination and / or neutralization of oxidative stress proteins.

[0091] In the case of immunotherapy, today's active and passive immunotherapy treatments carry a significant risk of encephalitis or systemic neuronal inflammation. By utilizing immunotherapy components in a fixed immunoaffinity approach, the CSF can be presented to antibodies, preventing any risk of initiating a systemic immune response against self. Furthermore, this also eliminates the risk of autoantibodies to systemically delivered immunotherapy, which can have devastating effects and high mortality in a subset of patients. A cartridge-based scheme allows for more rapid replacement of conditioning approaches.

[0092] These methods contemplate periodic reuse or recharging of the filtration / processing components of the system. For example, in ex-vivo immunotherapy approaches, specific eluents can be used to release captured oligomers or proteins and regenerate active antigen binding sites on the antibodies. Furthermore, the eluted compounds become purified human proteins that can then be used as "neurologic" agents. For example, in the case of Alzheimer's disease, the purified Aβ or tau components can then be released and used for a variety of other commercial or research investigations into the structure-function activity of disease-specific compounds in human diseases. Also contemplated is the ability to automatically or periodically collect CSF or specific subcomponents and store / freeze to generate CSF banks for specific disease processes.

[0093] The conditioned endogenous CSF is then returned to a different location from where it was drawn back into the CSF space. The second location or distal port for outflow or drainage is located sufficiently different from the location of the first location or proximal port for inflow or injection to create a mixture of conditioned and unconditioned CSF throughout the majority of the CSF space. For example, at least about 50%, 60%, 70%, 80%, 90% of the conditioned and unconditioned CSF in the CSF space can be mixed. The inflow and outflow ports can usually be at least two vertebrae apart, for example, when both ports are in the spinal cord region. In other embodiments, one of the inflow or outflow ports can be in the spine (e.g., sacral, lumbar, thoracic, or cervical), and the other inflow or outflow port can be in the subarachnoid or ventricular space. In some embodiments, both the inflow and outflow ports are in the ventricular space, e.g., the inflow port is in the first ventricle and the outflow port is in the second ventricle (dual ventricular embodiment). Depending on the design of the system, the quantitative distance between the inflow and outflow ports may be at least about 4 cm, e.g., at least about 5 cm, 8 cm, 10 cm, 12 cm, 15 cm, 20 cm, 30 cm, 40 cm, 50 cm, or 60 cm or more, depending on the length of the spine of the individual patient.

[0094] As described above and herein, one or more different geometries in the distal portion of the outflow lumen of the catheter promote turbulent mixing after return of the conditioned CSF. For example, the distal portion of the outflow lumen can be configured to be a uni- or bi-dimensional helical conformation, contain multiple exit ports (i.e., side holes or ports), have a textured (e.g., bumps, ridges, etc.) surface that induces turbulence, and have balloons, bellows, vanes, or turbines. T-shaped catheter configurations also find use. Flow velocity can also be increased in the distal portion of the outflow lumen, for example, by high pressure injection or jetting.

[0095] In the case of parallel processing, the removal or collection step and the return step can be performed simultaneously. This allows for a closed system and continuous processing or conditioning of the CSF, which is an advantage described herein. Overall, the inflow and outflow rates can be equal or substantially equal. As described above for these systems, the active flow can be maintained using a pump. The active flow rate can be uniform or discontinuous, as desired. The direction of the CSF flow path can also be reversed periodically, intermittently, or throughout the treatment period, so that the inflow port becomes the outflow port and the outflow port becomes the inflow port.

[0096] In addition to removing specific toxins from the CSF, the method also contemplates the delivery of therapeutic agents on the return cycle. That is, after a given volume has passed through a targeted specific purification scheme, specific pharmacological agents or drugs can be administered directly to the CNS, bypassing the blood-brain barrier. This provides an opportunity for specific delivery of pharmaceuticals to the CNS without many of the systemic side effects that are often associated with oral or intravenous delivery. One of the challenges of drug delivery via the CSF is designing drugs that penetrate the brain / spinal cord parenchyma. A variety of methods can be envisioned, including the use of hydrophobicity tuning or liposome-based approaches in conjunction with the system described herein. Thus, for the first time, the system described herein allows the combination of removing specific toxins and delivering specific therapeutic agents to the CNS.

[0097] The method also contemplates the injection of artificial CSF fluid into the system at any time, if desired. In addition to the purification of purified CSF, a combination of CSF purification and artificial CSF return, with appropriate physical / chemical protection, is just one possibility. The system can also be primed with such a physiologically compatible, artificial CSF solution. b. Methods of alleviating a disease state i. Alzheimer's disease (AD) Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by abnormal accumulation of amyloid plaques and neurofibrillary tangles. The formation of amyloid plaques is believed to be due, in part, to failure to clear beta-amyloid protein (Aβ). APP (amyloid precursor protein) generates various forms of amyloid-β by enzymatic processing. See Blennow, K., MJ de Leon et al. (2006) Lancet 368(9533):387-403. Diffusible oligomers of Aβ (from plaques) inhibit long-term potentiation, cause membrane damage, alter membrane fluidity, and act as a pore-forming toxin. See Caughey, B and PT Lansbury (2003) Annu Rev Neurosci 26:267-98; and Glabe, CG (2006) Neurobiol Aging 27(4):570-5. In AD, tau protein also aggregates, resulting in degeneration of neuronal axons and dendrites and producing neurofibrillary tangles. Accumulation of tau protein leads to cellular oxidative stress, which may be a causative factor in tau-induced neurodegeneration. See Dias-Santagata, D., TA Fulga et al. (2007) J Clin Invest 117(1):236-45. Specifically, highly reactive oxygen species oxidize lipids, proteins and DNA, resulting in tissue damage and cell death. These markers of oxidized lipids and proteins accumulate in areas that are particularly affected in neurodegenerative diseases. Markers of oxidative damage have been detected in brain tissue from patients with AD and other neurodegenerative disorders. Koo, EH, PT Lansbury, Jr. et al. (1999) Proc Natl Acad Sci See USA 96(18):9989-90. Free radical damage also appears to be a fundamental pathophysiological mediator of tissue damage in human diseases, including acute ischemic stroke, amyotrophic lateral sclerosis, Parkinson's disease, and AD. See Taylor, JP, J. Hardy et al. (2002) Science 296(5575):1991-5. Current therapies for AD are of limited efficacy because they fail to slow the rate of neurodegeneration, are associated with significant side effects, and some (immunization strategies) are only temporary at best.

[0098] In contrast, the processing of amyloid and tau proteins by CSF and the neutralization of reactive oxidative species are both symptomatic and disease-modifying therapies, due in particular to their ability to reduce, limit and prevent the formation of plaques and tangles, and their ability to combat neuroinflammation.This has the ability to address disease processes from multiple different perspectives based on the current understanding of pathogenesis.It may also be safer, since it has lower risks of liver damage and brain inflammation compared to current pharmacological and immunological therapies, respectively.

[0099] Thus, the methods alleviate or reduce the symptoms of Alzheimer's disease by reducing or eliminating the presence of beta-amyloid protein and / or tau protein in CSF using the system described herein. These methods include removing CSF from the patient as described herein; removing at least one of pathological proteins, including Aβ and tau, and inflammatory mediators (e.g., cytokines, including TNF-α, IL-1, IL-2, IL-6, IL-12, interferon-γ, etc.) from the CSF, and returning endogenous CSF to the patient, the removing and returning steps being performed simultaneously during at least a portion of the treatment. In some embodiments, Aβ or tau protein and / or inflammatory mediators are removed from the CSF using an immunoaffinity column or a size exclusion column or both.

[0100] In another embodiment, the methods include introducing a catheter device into the CSF space of the patient's spinal cord through a spinal cord access site; advancing the catheter device through the CSF space of the spinal cord and into the skull towards the brain such that distal and proximal ports on the catheter device are positioned within the CSF space and spaced a preselected distance apart or adjusted to an appropriate distance; withdrawing CSF through one of said ports; removing at least one of Aβ or tau protein or inflammatory mediators from the withdrawn CSF, thereby conditioning the CSF; and returning the conditioned CSF through the other of said ports, thereby alleviating or reducing a symptom of Alzheimer's disease.

[0101] Further embodiments for treating Alzheimer's disease are as discussed above and herein. ii. Parkinson's disease (PD) Parkinson's disease (PD) is caused by the loss of dopamine-containing pigmented neurons in the substantia nigra. Free radical damage and the formation of alpha-synuclein fibrils and oligomers (i.e., peptides) are involved in the pathogenesis of PD. See Steece-Collier, K., E. Maries et al. (2002) Proc Natl Acad Sci USA 99(22):13972-4. Current treatments (dopamine replacement therapy with L-dopa, catechol-O-methyltransferase (COMT) inhibitors, amantadine and anticholinergics for symptom relief, surgery with deep brain stimulation) have no long-term efficacy, do not address the cause of the disease, and may be associated with debilitating side effects, including dyskinesias. See Dunnett, SB and A. Bjorklund (1999) Nature 399(6738 Suppl):A32-9; Dawson, TM and VL Dawson (2003) Science 302(5646):819-22; and DeKosky, ST and K. Marek (2003) Science 302(5646):830-4. There is a need for treatments that halt degeneration by removing free radicals and neurotoxic species. See Shoulson, I. (1998) Science 282(5391):1072-4. Filtration of CSF fulfills this unmet medical need and may be a disease-modifying mechanism for the treatment of new PD.

[0102] Thus, the method uses the system described herein to alleviate or reduce the symptoms of Parkinson's disease by reducing or eliminating the presence of alpha-synuclein fibrils and / or oligomers in CSF.These methods include removing CSF from a patient as described herein; removing at least one of alpha-synuclein protein and inflammatory mediators from the CSF, and returning endogenous CSF to the patient, the removing and returning steps being performed simultaneously during at least a portion of the treatment.In some embodiments, alpha-synuclein fibrils and oligomers are removed from CSF using an immunoaffinity column or a size exclusion column or both.

[0103] In another embodiment, these methods include introducing a catheter device into the CSF space of the patient's spinal cord through a spinal cord access site; advancing the catheter device skull through the CSF space of the spinal cord towards the brain such that distal and proximal ports on the catheter device are positioned within the CSF space and spaced a preselected distance apart or adjusted to an appropriate distance; withdrawing CSF through one of said ports; removing at least one of alpha-synuclein protein and inflammatory mediators from the withdrawn CSF, thereby conditioning the CSF; and returning the conditioned CSF through the other of said ports, thereby alleviating or reducing symptoms of Parkinson's disease.

[0104] Further embodiments for treating Parkinson's disease are as discussed above and herein. iii. Amyotrophic lateral sclerosis (ALS) Amyotrophic lateral sclerosis (ALS) / Lou Gehrig's disease is a rapidly progressive, invariably fatal disease of motor neurons that attacks nerve cells involved in controlling voluntary muscles. See Rowland, LP (1995) Proc Natl Acad Sci USA 92(5):1251-3. Both upper and lower motor neurons degenerate or die and stop sending messages to muscles. ALS patients have higher levels of glutamate in their serum and spinal fluid. Laboratory studies have demonstrated that nerve cells begin to die when exposed to excessive amounts of glutamate for extended periods of time. See Rowland, LP (1995) Proc Natl Acad Sci USA 92(5):1251-3. Increased levels of neurofibrillary proteins and antibodies against GM1-ganglioside, AGM1-ganglioside and sulfatide were found in 20%, 15% and 8% of CSF of ALS patients, respectively. See Valentine, JS and PJ Hart (2003) Proc Natl Acad Sci USA 100(7):3617-22; and Banci, L., I. Bertini et al. (2007) Proc Natl Acad Sci USA 104(27):11263-7. Thus, antibodies may be implicated in ALS by impairing motor neuron function and disrupting signal transmission between brain and muscle. Free radical damage may also be involved in ALS. 4-Hydroxynonenal (HNE), a marker of oxidative stress and lipid peroxidation, was elevated in the CSF of patients with sporadic ALS. The current clinical treatment for ALS (riluzole), which reduces the amount of glutamate released, does not reverse the damage already done to motor neurons and causes side effects such as liver toxicity. In the case of ALS, purification of the CSF would lower the excessively high levels of glutamate in the CSF and reduce oxidative species, thereby extending the lifespan of motor neurons and removing autoimmune antibodies and reactive oxidative species from the CSF without significant side effects such as liver damage.

[0105] Thus, the methods use the systems described herein to alleviate or reduce symptoms of amyotrophic lateral sclerosis (ALS) by reducing or eliminating the presence of one or more of insoluble superoxide dismutase-1 (SOD1), glutamic acid, neurofibrillary proteins, and anti-GM1 ganglioside antibodies in the CSF. These methods include removing CSF from a patient as described herein; removing at least one of insoluble superoxide dismutase-1 (SOD1), glutamic acid, neurofibrillary proteins, and anti-GM1 ganglioside antibodies or other inflammatory mediators from the CSF; and returning endogenous CSF to the patient, the removing and returning steps being performed simultaneously during at least a portion of the treatment. In some embodiments, insoluble superoxide dismutase-1 (SOD1), glutamate, neurofibrillary proteins, anti-GM1 ganglioside antibodies or other inflammatory mediators are removed from the CSF using one or more of an immunoaffinity column, a size exclusion column, an anion exchange column, a cation exchange column and a Protein A or Protein G column.

[0106] In another embodiment, the methods include introducing a catheter device into the CSF space of the patient's spinal cord through a spinal cord access site; advancing the catheter device through the CSF space of the spinal cord toward the brain such that distal and proximal ports on the catheter device are positioned within the CSF space and spaced a preselected distance apart or adjusted to an appropriate distance; withdrawing CSF through one of said ports; removing at least one of insoluble superoxide dismutase-1 (SOD1), glutamate, neurofibrillary protein, anti-GM1 ganglioside antibodies or other inflammatory mediators from the withdrawn CSF, thereby conditioning the CSF; and returning the conditioned CSF through the other of said ports, thereby alleviating or reducing symptoms of amyotrophic lateral sclerosis (ALS).

[0107] Further embodiments for treating amyotrophic lateral sclerosis (ALS) are as discussed above and herein. iv. Cerebral vasospasm Cerebral vasospasm is a time-dependent narrowing of the diameter of cerebral blood vessels thought to be due to blood in the subarachnoid space (after ruptured cerebral aneurysm, subarachnoid hemorrhage (SAH), craniocerebral trauma, bacterial meningitis, after sellar / parasellar surgery, etc.). Macdonald, RL, RM See Pluta et al. (2007) Nat Clin Pract Neurol 3(5):256-63. Hemolysis is necessary for vasospasm to develop, and oxyhemoglobin is thought to be one of many vasoactive substances released. Elevated levels of oxyhemoglobin in the CSF are maintained throughout the period of vasospasm. In contrast, most other vasoactive substances released after clot lysis are rapidly cleared from the CSF. Macdonald, RL, RM See Pluta et al. (2007) Nat Clin Pract Neurol 3(5):256-63. In subarachnoid patients with vasospasm, endothelin in the CSF was maintained at or above elevated levels measured preoperatively. This increase coincided with the appearance of vasospasm documented by transcranial Doppler and clinical symptoms. In SAH patients who did not develop vasospasm, the concentration of endothelin in the CSF decreased over time. See Macdonald, R. L, RM Pluta et al. (2007) Nat Clin Pract Neurol 3(5):256-63. Current therapies (calcium channel blockers, hypervolemic hypertensive therapy, and hemodilution (HHH therapy)) are ineffective in preventing vasospasm. It is more likely that CSF filtration is therapeutic due to early direct removal of clots, red blood cells, platelets, and the downstream cascade involving oxyhemoglobin and endothelin that leads to vasospasm.

[0108] Thus, the method uses the system described herein to alleviate or reduce the symptoms of cerebral vasospasm by reducing or eliminating the presence of one or more of blood cells (e.g., red blood cells), hemoglobin, oxyhemoglobin, endothelin, or other inflammatory mediators in the CSF.These methods include removing CSF from the patient as described herein; removing at least one of blood cells, hemoglobin, oxyhemoglobin, endothelin, or inflammatory mediators from the CSF, and returning endogenous CSF to the patient, the removing and returning steps being performed simultaneously during at least a portion of the treatment.In some embodiments, the oxyhemoglobin and endothelin are removed from the CSF using one or more of an immunoaffinity column, a size exclusion column, an anion exchange column, and a cation exchange column.

[0109] In another embodiment, these methods include introducing a catheter device into the CSF space of the patient's spinal cord through a spinal cord access site; advancing the catheter device through the CSF space of the spinal cord toward the brain such that distal and proximal ports on the catheter device are positioned within the CSF space and spaced a preselected distance apart or adjusted to an appropriate distance; withdrawing CSF through one of said ports; removing at least one of blood cells, hemoglobin, oxyhemoglobin, endothelin or other inflammatory mediators from the withdrawn CSF, thereby conditioning the CSF; and returning the conditioned CSF through the other of said ports, thereby alleviating or reducing the symptoms of cerebral vasospasm.

[0110] Further embodiments for treating cerebral vasospasm are as discussed above and herein. v. Encephalitis Encephalitis is an inflammation of the brain with multiple causes: HSV (herpes simplex virus), Lyme disease, syphilis, bacterial infections, etc. Infants under 1 year of age and adults over 55 years of age are at increased risk of death from encephalitis. See Vernino, S., M. Geschwind et al. (2007) Neurologist 13(3):140-7. Current therapies (adrenal steroids to reduce brain swelling and NSAIDs to reduce fever) do not target the cause of encephalitis. Levels of sTNF-R (reflecting the biological activity of TNF-alpha, the main inflammatory mediator) were significantly higher in the CSF and serum of children with acute encephalitis compared with those of control subjects. Vernino, S., M. See Geschwind et al. (2007) Neurologist 13(3):140-7. IgG levels were increased in herpes simplex encephalitis. See Vernino, S., M. Geschwind et al. (2007) Neurologist 13(3):140-7. Treatment of CSF could restore TNF-alpha and IgG levels to physiological levels, reduce inflammation, and aid in the elimination of viruses, parasites, prions, fungi, and bacteria. Further applications include treating victims of biological weapons (anthrax, botulinum, ricin, saxitoxin, etc.) by directly removing the targeted toxin from the attacked CNS.

[0111] Thus, the methods alleviate or reduce symptoms of encephalitis by reducing or eliminating the presence of one or more of tumor necrosis factor-alpha (TNFα) and IgG in the CSF using the systems described herein. These methods include removing CSF from the patient as described herein; removing at least one of TNFα and IgG or other inflammatory mediators from the CSF, and returning endogenous CSF to the patient, the removing and returning steps being performed simultaneously during at least a portion of the treatment. In some embodiments, TNFα and IgG are removed from the CSF using one or more of an immunoaffinity column, a size exclusion column, an anion exchange column, a cation exchange column, and a protein A or protein G column.

[0112] In another embodiment, these methods include introducing a catheter device into the CSF space of the patient's spinal cord through a spinal cord access site; advancing the catheter device through the CSF space of the spinal cord toward the brain such that distal and proximal ports on the catheter device are positioned within the CSF space and spaced a preselected distance apart or adjusted to an appropriate distance; withdrawing CSF through one of said ports; removing at least one of TNFα and IgG or other inflammatory mediators from the withdrawn CSF, thereby conditioning the CSF; and returning the conditioned CSF through the other of said ports, thereby alleviating or reducing the symptoms of encephalitis.

[0113] Further embodiments for treating encephalitis are as discussed above and herein. vi. Guillain-Barre Syndrome (GBS) Guillain-Barre syndrome (GBS) is divided into two major subtypes: acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). See Parkhill, J., BW Wren et al. (2000) Nature 403(6770):665-8; and Yuki, N., K. Susuki et al. (2004) Proc Natl Acad Sci US A 101(31):11404-9. In Europe and North America, GBS is usually caused by AIDP, with prominent lymphocytic infiltration of peripheral nerves and invasion of myelin and Schwann cells by macrophages. Activated complement found in the cerebrospinal fluid of Guillain-Barre and multiple sclerosis (MS) patients may contribute to demyelination. See Parkhill, J., BW Wren et al. (2000) Nature 403(6770):665-8; and Yuki, N., K. Susuki et al. (2004) Proc Natl Acad Sci USA 101(31):11404-9. Treatment of GBS is further divided into symptom management in severely paralyzed patients who require intensive care and ventilatory support, and specific disease therapy to reduce neurological damage. Immunomodulatory therapies such as plasma exchange and intravenous immunoglobulin are indicated for patients who are not able to walk independently. Results of international randomized trials have shown comparable efficacy between both plasma exchange and intravenous immunoglobulin, while corticosteroids are ineffective. See McKhann, GM, JW Griffin et al. (1988) Ann Neurol 23(4):347-53; and Kuwabara, S., M. Mori et al. (2001) Muscle Nerve 24(1):54-8. Repeated CSF filtration can remove pathogenetically relevant cells, immunoglobulins, and polypeptides. Observations of 12 severely ill Guillain-Barre patients treated with CSF filtration indicate that this is a safe and effective procedure. CSF filtration and plasma exchange are at least equally efficacious, and patients with severe disease who did not respond to plasma exchange achieved complete recovery with CSF filtration. Wollinsky, K. See Wollinsky, KH, PJ Hulser et al. (2001) Neurology 57(5):774-80. Filtration of CSF (in vitro studies) effectively removed cells and inflammatory mediators (e.g., C5a, TNF-α, IL-2, IL-6, interferon-γ, IgG, endotoxins, and cells). See Wollinsky, KH, PJ Hulser et al. (2001) Neurology 57(5):774-80. Thus, studies indicate that filtration of CSF is at least as effective as plasma exchange in reducing, limiting, and preventing neuronal damage by removing lymphocytes, macrophages, complement proteins, and other inflammatory agents.

[0114] Thus, the methods alleviate or reduce symptoms of Guillain-Barre Syndrome (GBS) by reducing or eliminating the presence in the CSF of cells and one or more of an inflammatory mediator selected from the group consisting of C5a, TNF-α, IL-2, IL-6, interferon-γ, IgG, and endotoxin using the systems described herein. These methods include removing CSF from a patient as described herein; removing cells and at least one of an inflammatory mediator selected from the group consisting of C5a, TNF-α, IL-2, IL-6, interferon-γ, IgG, and endotoxin from the CSF, and returning endogenous CSF to the patient, wherein the removing and returning steps are performed simultaneously during at least a portion of the treatment. In some embodiments, cells and inflammatory mediators selected from the group consisting of C5a, TNF-α, IL-2, IL-6, interferon-γ, IgG, and endotoxins are removed from the CSF using one or more of an immunoaffinity column, a size exclusion column, an anion exchange column, a cation exchange column, and a Protein A or Protein G column.

[0115] In another embodiment, the methods include introducing a catheter device into the CSF space of the patient's spinal cord through a spinal access site; advancing the catheter device through the CSF space of the spinal cord toward the brain such that distal and proximal ports on the catheter device are positioned within the CSF space and spaced a preselected distance apart or adjusted to an appropriate distance; withdrawing CSF through one of said ports; removing cells and at least one of inflammatory mediators selected from the group consisting of C5a, TNF-α, IL-2, IL-6, interferon-γ, IgG, and endotoxin from the withdrawn CSF, thereby conditioning the CSF; and returning the conditioned CSF through the other of said ports, thereby alleviating or reducing symptoms of Guillain-Barre Syndrome (GBS).

[0116] Further embodiments for treating Guillain-Barre syndrome are as discussed above and herein. vii.Multiple Sclerosis (MS) Multiple sclerosis (MS) is the most common demyelinating disease in humans and the etiology is unknown. However, it is widely accepted that it is an autoimmune disease mediated by autoreactive T lymphocytes with specificity for myelin antigens. See Noseworthy, JH (1999) Nature 399 (6738 Suppl): A40-7. The pathological hallmark of the disease is the MS plaque, which is an area of ​​demyelination of the white matter usually accompanied by an inflammatory infiltrate consisting of T lymphocytes, some B cells and plasma cells, activated macrophages, or microglial cells. IgG and complement are localized mainly at the periphery of the plaques. Clones of B lymphocytes accumulate in the CSF of patients with MS and other neurological disorders. Anti-myelin-oligodendrocyte glycoprotein antibodies were detected in the CSF from seven patients with MS compared with two patients with other neurological disorders and one patient with tension headaches. See Hohlfeld, R. and H. Wekerle (2004) Proc Natl Acad Sci USA vol. 101 Suppl. 2: 14599-606. Increased numbers of CD4+ T helper cells can be found in the CSF during early exacerbations. Osteopontin has been found to be increased in patients' plasma before and during relapses, exacerbating autoimmune relapses and causing severe progression of myelinating disease. See Hohlfeld, R. and H. Wekerle (2004) Proc Natl Acad Sci USA vol. 101 Suppl. 2: 14599-606. Current therapies are limited and often ineffective, and include steroids, interferon beta therapy, treatment with monoclonal antibodies, and global immunosuppression mediated by peptide fragments that resemble myelin proteins. Purification of CSF has the advantage of depleting cell populations to mitigate the effects of MS exacerbations by 1) removing autoreactive CD4+ and CD8+ T cells, 2) reducing the levels of proinflammatory cytokines, and 3) reducing the production of autoreactive antibodies by B cells. Depletion of these autoreactive cell populations can also reduce the recurrence of MS exacerbations, limit the persistent inflammatory damage seen in exacerbations, and halt the lesions that characterize disease progression.By limiting this depletion to the CSF, the present systems and methods address these issues without many of the complications associated with steroid treatment or systemic immunosuppression.

[0117] Thus, the methods use the systems described herein to alleviate or reduce symptoms of multiple sclerosis (MS) by reducing or eliminating the presence in the CSF of one or more of T cells, B cells, anti-myelin antibodies, and inflammatory mediators selected from the group consisting of TNF-α, IL-2, IL-6, interferon-γ. These methods include removing CSF from a patient as described herein; removing at least one of T cells, B cells, anti-myelin antibodies, and inflammatory mediators selected from the group consisting of TNF-α, IL-2, IL-6, interferon-γ from the CSF, and returning endogenous CSF to the patient, wherein the removing and returning steps are performed simultaneously during at least a portion of the treatment. In some embodiments, T cells, B cells, anti-myelin antibodies, and inflammatory mediators selected from the group consisting of TNF-α, IL-2, IL-6, interferon-γ are removed from the CSF using one or more of an immunoaffinity column, a size exclusion column, an anion exchange column, a cation exchange column, and a protein A or protein G column.

[0118] In another embodiment, these methods include introducing a catheter device into the CSF space of the patient's spinal cord through a spinal cord access site; advancing the catheter device through the CSF space of the spinal cord toward the brain such that distal and proximal ports on the catheter device are positioned within the CSF space and spaced a preselected distance apart or adjusted to an appropriate distance; withdrawing CSF through one of said ports; removing at least one of T cells, B cells, anti-myelin antibodies, and inflammatory mediators selected from the group consisting of TNF-α, IL-2, IL-6, interferon-γ from the withdrawn CSF, thereby conditioning the CSF; and returning the conditioned CSF through the other of said ports, thereby alleviating or reducing symptoms of multiple sclerosis (MS).

[0119] Further embodiments for treating multiple sclerosis (MS) are as discussed above and herein. viii. Stroke Stroke occurs when a blood clot blocks an artery or a blood vessel breaks, interrupting blood flow to an area of ​​the brain; brain cells then begin to die and brain damage occurs. Free radical damage has been implicated in the pathogenesis of stroke. CSF enolase was increased in patients with transient ischemic attacks and in patients with complete stroke. See McCulloch, J. and D. Dewar (2001) Proc Natl Acad Sci US A 98(20):10989-91. High cerebrospinal fluid enolase has always been associated with poor prognosis. Endothelin-1 (ET-1), a highly potent endogenous vasoactive peptide, exerts a sustained vasoconstrictive effect on the blood vessels of the brain. See Mascia, L., L. Fedorko et al. (2001) Stroke 32(5):1185-90; and Kessler, IM, YG Pacheco et al. (2005) Surg Neurol 64(Suppl 1):S1:2-5; discussion S1:5. Elevations in plasma ET-1 have been reported 1 to 3 days after ischemic stroke. The mean CSF concentration of ET-1 in stroke patients was 16.06±4.9 pg / mL compared with 5.51±1.47 pg / mL in controls (P<.001). See Mascia, L., L. Fedorko et al. (2001) Stroke 32(5):1185-90; and Kessler, IM, YG Pacheco et al. (2005) Surg Neurol 64(Suppl 1):S1:2-5; discussion S1:5. Current management of stroke is ineffective and includes symptomatic treatment (surgery, inpatient care and rehabilitation) and carries the risk of cerebral hemorrhage (cerebral angioplasty and the use of tissue plasminogen activator (tPA) to dissolve acute clots in blood vessels). Similarly, traumatic brain injury (TBI) or spinal cord injury (SCI) occurs when a sudden trauma affects the brain or spinal cord after a fall, traffic accident, assault, etc. Current treatment of TBI and SCI focuses on increasing independence in daily life and rehabilitation (i.e., individual therapy).Moderate hypothermia is believed to limit deleterious metabolic processes that may exacerbate the injury. Processing of the CSF not only allows for the removal of neuroinflammatory components such as enolase, ET-1, and free radicals, but also provides selective cooling to the CNS that is expected to be more rapid and effective than whole-body cooling, which is limited by the risk of chills and severe cardiac arrhythmias.

[0120] Thus, the method uses the system described herein to alleviate or reduce the symptoms of stroke, traumatic brain injury (TBI), spinal cord injury (SCI) by reducing or eliminating the presence of one or more of endothelin and enolase or other inflammatory mediators in the CSF. These methods include removing CSF from the patient as described herein; removing at least one of endothelin and enolase from the CSF, and returning endogenous CSF to the patient, the removing and returning steps being performed simultaneously during at least a portion of the treatment. In some embodiments, the endothelin and enolase or other inflammatory mediators are removed from the CSF using one or more of an immunoaffinity column, a size exclusion column, an anion exchange column, a cation exchange column, and a protein A or protein G column. In some embodiments, the removed CSF is cooled to below physiological body temperature.

[0121] In another embodiment, the methods include introducing a catheter device into the CSF space of the patient's spinal cord through a spinal access site; advancing the catheter device skull through the CSF space of the spinal cord towards the brain such that distal and proximal ports on the catheter device are positioned within the CSF space and spaced a preselected distance apart or adjusted to an appropriate distance; withdrawing CSF through one of said ports; removing at least one of endothelin and enolase or other inflammatory mediators from the withdrawn CSF and / or cooling the CSF to various temperatures, thereby conditioning the CSF; and returning the conditioned CSF through the other of said ports, thereby alleviating or reducing symptoms of stroke, TBI, SCI.

[0122] Further embodiments for treating stroke are as discussed above and herein.

[0123] It will be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. 1. A system for conditioning cerebrospinal fluid (CSF), comprising: a catheter assembly including a first lumen having a plurality of inflow holes and a second lumen having a plurality of outflow holes, the catheter adapted to be introduced into a CSF space, the plurality of inflow holes and the plurality of outflow holes being axially spaced apart; a pump connectable between the first lumen and the second lumen for inducing flow of CSF therebetween; a conditioning component connectable between the first lumen and the second lumen for conditioning the flow of CSF therebetween; Equipped with the catheter assembly is configured to withdraw CSF through the plurality of inflow holes and return CSF through the plurality of outflow holes at substantially the same rate. system.

2. The system of claim 1 , wherein the pump has an adjustable flow rate between 0.04 ml / min and 30 ml / min.

3. The system of claim 1 , wherein the pump comprises a peristaltic pump that is isolated from the flow of CSF.

4. The system of claim 1 , wherein the conditioning component is selected from the group including size exclusion, immunoaffinity, biospecific affinity, cation exchange, anion exchange, and hydrophobicity.

5. The system of claim 1 having a CSF holding volume of less than 40 ml.

6. The system of claim 1 , wherein the conditioning component is configured to remove at least one of red blood cells, hemoglobin, oxyhemoglobin, and endothelin from the CSF.

7. The system of claim 1 , wherein the conditioning component is configured to remove at least one of alpha-synuclein fibrils and oligomers from the CSF.

8. The system of claim 1 , wherein the conditioning component is configured to remove at least one of insoluble superoxide dismutase-1 (SOD1), glutamic acid, neurofilamentous proteins, and anti-GM1 ganglioside antibodies from the CSF.

9. The system of claim 1 , wherein the conditioning component is configured to remove at least one of tumor necrosis factor-alpha (TNFα) and IgG from the CSF.

10. 2. The system of claim 1, wherein the conditioning component is configured to remove at least one of: cells; and inflammatory mediators selected from the group consisting of C5a, TNFα, IL-2, IL-6, interferon-γ, IgG; and endotoxins from the CSF.

11. 2. The system of claim 1, wherein the conditioning component is configured to remove from the CSF at least one of T cells, B cells, anti-myelin antibodies; and inflammatory mediators selected from the group consisting of TNF-α, IL-2, IL-6, and interferon-γ.

12. The system of claim 1 , wherein the conditioning component is configured to remove at least one of endothelin and enolase from the CSF.

13. 2. The system of claim 1, wherein the catheter assembly comprises a single tubular member having (a) the first lumen and the plurality of inflow holes, and (b) the second lumen and the plurality of outflow holes fixedly disposed therein.

14. 2. The system of claim 1, wherein the system is configured to periodically reverse a flow direction removing the cerebrospinal fluid and a flow direction returning the conditioned cerebrospinal fluid such that the CSF is withdrawn from the plurality of outlet holes and returned through the plurality of inlet holes.

15. The system of claim 1 , wherein the catheter assembly comprises a plurality of tubular members.

Images