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). Even 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 CSF spaces (ventricles, spinal column) to other parts of the body (e.g., abdomen, peritoneal cavity). See, e.g., U.S. Patent Nos. 2,969,066; 3,889,687; 6,575,928; and 7,118,549. Other patents describe administering therapeutic agents to CSF spaces but do not disclose removal of CSF. See, e.g., U.S. Patent Nos. 5,531,673; 6,056,725; 6,594,880; 6,682,508; and 6,689,756. Generally, 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 or 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 location 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 intracranial and intraspinal CSF volume. 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. 5,629,299; U.S. Patent No. 5,629,299; and U.S. Patent No. 5,629,299. This method can dilute, but not eliminate, the concentration of toxic species. It has been proposed to treat drug overdose or remove tumor cells by removing debris and then implanting a ventriculoperitoneal shunt system. Such devices are unnatural in that they do not remove targeted toxins from the patient's endogenous CSF but require the entire system to be flushed with an artificially generated solution; they require the injection and regular delivery of many liters of replacement fluid; they do not target or focus on the removal of specific targeted toxins; and they are only practical in acute situations where many liters of fluid can be injected. See, for example, U.S. Patent No. 5,629,299.

[0007] Although various devices exist that aim 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 methods and systems for treating and removing one or more target compounds from a patient's CSF. Recently, a modified ventriculoperitoneal shunt system has been used to treat Alzheimer's disease by diverting fluid from the brain (ventricular system) to another part of the patient's body (e.g., the abdominal / peritoneal cavity) to remove CSF. See, for example, U.S. Patent Nos. 5,629,997 and 5,729,997. The rationale is that continuously draining CSF at a low rate, forcing the body to produce new CSF daily, dilutes the concentration of contaminants remaining in the endogenous CSF. Such systems have several inherent limitations. The rate at which toxic species are reduced is mediated by passive flow, which is very slow; only a small fraction of the total CSF volume (a few milliliters) is addressed per hour; they do not target or focus their removal on specific items of interest; and they do not prevent reabsorption of toxic species back into the systemic circulation, resulting in their return to the CSF. See, for example, U.S. Patent Nos. 5,629,997; 5,729,997; and 5,729,997.

[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 comprise: a) removing CSF from a first location in the patient's CSF space; 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, the methods comprising: a) introducing a catheter device into the CSF space of the patient's spinal cord through an accessible 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 (toward the brain) so that the distal and proximal ports 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, the 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 so 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 the ventricles 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 that which would cause spinal headache 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 and second locations 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 and second locations is at least about two vertebrae apart.

[0019] In some embodiments, the first location or proximal port is at or above the sacral vertebra S1 or lumbar vertebra L5, and the second location is at or above the lumbar vertebra 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 of the brain. 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, at 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 located in the ventricular space. For example, the first location or proximal port and the second location or distal port may be located on opposite sides of one ventricle. In another example, the first location or proximal port is located in the first ventricle, and the second location or distal port is located 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 direction of flow for removing or withdrawing CSF and the direction of flow for returning CSF are periodically reversed so that CSF is returned to a first location and removed from a second location during a portion of the procedure, for example, the flow reversal is a pulse to clear debris from the removal or return port.

[0024] In some embodiments, the methods further include mixing the conditioned CSF with unconditioned CSF upon returning the conditioned CSF to the CSF space. In some embodiments, the methods include inducing turbulence to enhance mixing upon returning the conditioned CSF. For example, turbulence can be created by introducing one or more spiral channels, textured (e.g., ribbed or knobby) channels, T-shaped separation channels, bellows, balloons, vanes, and / or multi-lumen catheters containing 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 comprises removing target molecules (e.g., proteins, peptides, oligopeptides) from the CSF. For example, conditioning can comprise 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 includes 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 the distal port and another lumen connected to the 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 alleviating 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 using the methods and systems described above and herein.

[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 entity, 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-Barré 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 endotoxin 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, the 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 therefore 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, the catheter adapted to be introduced into the CSF space, the ports being axially spaced apart; ii) a pump connectable between the first lumen and the second lumen for causing flow of CSF therebetween; iii) a conditioning component connectable between the first lumen and the second lumen for conditioning the flow of CSF therebetween; 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, and 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., 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. 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 component can be of any type, for example, a membrane, nanoparticle, flat surface, tube, or capillary.

[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. In 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 region that is in contact with any component of the nervous system but not within the tissues. Interstitial fluid is found within tissues.

[0048] The phrases "conditioning CSF" or "conditioned CSF" refer interchangeably to CSF that has been partially, mostly, 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 items. (Item 1) 1. A method for conditioning cerebrospinal fluid (CSF) in a patient, comprising: removing CSF from a first location in the patient's CSF space; 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 item 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) Item 10. The method of claim 1, wherein the distance between the first location and the second location is at least 4 cm. (Item 6) Item 6. The method of item 5, wherein the first location is at or above S1 and the second location is at or above L3. (Item 7) Item 7. The method of item 6, wherein the second location is in the CSF space of the cervical spine. (Item 8) Item 7. The method of item 6, wherein the second location is in a ventricle. (Item 9) Item 14. The method of item 1, wherein the direction of flow removing and returning CSF is periodically reversed such that CSF is returned to the first location and removed from the second location during a portion of the treatment. (Item 10) 10. The method of claim 9, wherein the flow reversal is a pulse to remove debris from a removal or return port. (Item 11) 10. The method of claim 1, further comprising the step of mixing the conditioned CSF with endogenous CSF when returning the conditioned CSF to the CSF space. (Item 12) Item 12. The method of item 11, wherein the mixing step includes inducing turbulence in returning the conditioned CSF. (Item 13) Item 10. The method of claim 1, wherein the conditioning step comprises removing the target molecule. (Item 14) Item 14. The method of item 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) 17. The method of claim 1, wherein the conditioning step is performed external to the patient's body. Item 10. The method of item 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 so 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. A method comprising: (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) Item 19. The method of item 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) 19. 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, a spiral catheter, a T-catheter, a bellows, a ribbed catheter, a vane, and a balloon. (Item 25) 1. A method for conditioning cerebrospinal fluid in a patient, comprising: introducing a catheter device into the 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. A method comprising: (Item 26) Item 26. The method according to item 25, wherein the distance 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) Item 26. The method according to item 25, wherein the step of adjusting the spacing between the pair of ports includes 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 to be introduced into the CSF space, the ports being axially spaced apart; a pump connectable between the first lumen and the second lumen for causing 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) Item 31. The system of item 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 a flow rate adjustable 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 capacity of less than 40 ml. (Item 38) 31. The system of item 30, which is implantable. (Item 39) 1. A method of alleviating symptoms of Alzheimer's disease in a patient, comprising: removing CSF from a first location in the patient's CSF space; 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 patient's CSF space; 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 patient's CSF space; 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 symptoms of cerebral vasospasm in a patient, comprising: removing CSF from a first location in the patient's CSF space; 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 patient's CSF space; 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-Barré syndrome (GBS) in a patient, comprising: removing CSF from a first location in the patient's CSF space; 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 patient's CSF space; 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 patient's CSF space; 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 explanation of the drawings]

[0050] [Figure 1] Sagittal sections of the brain and spinal cord are shown, 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. [Figure 2] A) View of the ventricular system from the lateral surface, B) anterior surface, C) superior surface, and D) detailed ventricular structure. [Figure 3] FIG. 1 shows a three-dimensional view of the anatomy of the ventricles. [Figure 4] Diagram showing the blood-brain barrier and blood-CSF barrier. A) Fenestrated capillaries that allow water and solutes to pass through. 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. [Figure 5]

[0013] Figure 1 illustrates the oligomer hypothesis of neurodegenerative disease. A multi-step process is thought to underlie many different neurological conditions. Disease-specific proteins undergo specific biochemical modifications that predispose them to combine and form globular intermediates known as oligomers. These oligomers, which are thought to be toxic, can subsequently stack with each other to form protofibrils and fibrils. 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] Schematic diagram showing ventricular, spinal and ventriculo-spinal approaches to access the CSF space for efficient rotation 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 showing a dual-chamber system of the present invention. Multi-chamber systems create active, dynamic flow, with relatively equal inflow and outflow, resulting in efficient mixing that is not limited by pressure volume. This allows for parallel processing of CSF with maximum rotation, providing access to the cranial and spinal spaces and all CSF volumes (shading indicates mixing). [Figure 8-2] (FIG. 8B) The dramatic difference in CSF clearance afforded by a multi-lumen 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-lumen and multi-lumen catheters for use in the CSF space. These are just 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 CSF. [Figure 10] Figures 10A and 10B show catheters with helical outflow paths that induce additional mixing at various outflow points. Figure 10A shows a single helical outflow path over the final length (1) of the catheter. A straight outflow lumen connects to the helical path. The catheter contains a straight inflow lumen at its center. Figure 10B shows a double helical outflow path catheter with an inflow path at its 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 pumping 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 pathways change direction as another means of creating directional flow. [Figure 12] Figure 12A shows two catheters joined by a double loop. The loop is fixed to one catheter and slides over the other catheter, allowing the distance "d" between the two ends to be adjusted. In this case, the inflow catheter connects to the sliding portion of the loop. Figure 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 access to the ventricles. The holes surrounded by the parenchyma are blocked by the parenchyma. These include overlapping portions. Figure 14B shows a close-up of the distal end, showing one overlapping hole on the left. Figure 14C shows a central section showing the overlapping holes. [Figure 15] Figure 15A shows the distal section. Figure 15B shows a catheter incorporating multiple balloons. Inflow and outflow lumens are visible on either side of the proximal "T-section." The balloon inflation lumen is located above the T-section. Three balloon inflation ports are visible from above through the thin membrane that forms the balloon. Figure 15C is a cross-sectional view 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 uniform or of different lengths. DETAILED DESCRIPTION OF THE INVENTION

[0051] 1. Introduction The present invention provides methods, devices, and systems for removing, detecting, returning, and delivering compounds to and / or from the cerebrospinal fluid (CSF) space of a patient. Specific compound removal and / or delivery can be tailored to specific disease conditions. Removal is targeted and specific, for example, through 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, rational therapeutic platform for treating a variety of debilitating and often devastating neurological disorders that currently have limited and ineffective treatment options. Examples of disease states treatable by the present CSF treatment systems and methods include, but are not limited to, cerebral vasospasm, Guillain-Barré 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, and biological weapons. For the first time, the present invention provides patients with a disruptive technology that addresses known etiologies and effectively alleviates symptoms and modifies disease for numerous neurological conditions.

[0053] CSF: Cerebrospinal fluid (CSF) is primarily produced 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 itself and the interstitial fluid of the nervous system. Water and soluble substances are freely exchanged between the CSF and the nervous system. Thus, many neurotransmitters, peptides, and other neurotropic substances can be found in the CSF. The functional roles of many of these peptides are currently being investigated. The concentrations of various neurotropic substances in the CSF are of great interest because they indirectly reflect the conditions in the extracellular fluid immediately adjacent to neurons in the brain and spinal cord. Thus, the CSF serves two main functions: 1) by coating the brain and spinal cord, the CSF provides protection, providing buoyancy and preventing traction on blood vessels and nerves during impacts against the skull or spinal column; and 2) perhaps even more importantly, the CSF contributes to maintaining 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 approximately 0.3 ml / min, 18 ml / hr, or approximately 432 ml / day. However, the total volume found in the ventricles and subarachnoid space is approximately 150 ml (Figure 2). Thus, the total volume of CSF turns over several times (approximately three times) each day. Fluid produced in the lateral ventricles flows into the third ventricle through the interventricular foramen (foramen of Monro) and then into the fourth ventricle through the narrow cerebral aqueduct (Figure 3). From there, CSF exits either posteriorly (foramen of Magendie) or laterally (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 through 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 through capillary walls relatively easily, and thus their concentrations in plasma are similar to those in interstitial (extracellular) fluid. Due to selective properties of brain capillaries, known as the blood-brain barrier (BBB), the composition of interstitial fluid in the CNS differs from that in most other organs. This barrier consists of extensive, tight junctions between endothelial cells, preventing the passage of many substances from peripheral plasma (Figure 4). Similar to the BBB, the epithelium of the choroid plexus represents an additional barrier between blood and CSF, known as the blood-CSF barrier. Therefore, many substances that can exit the choroid plexus capillaries cannot enter the CSF. Normal function of neurons depends on 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 a growing 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 and prevention or mitigation of disease processes. Furthermore, systems can be tailored 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 disorders share common underlying disease mechanisms. This presents an opportunity for intervention using a device platform that addresses multiple distinct 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) and "exogenous pathogens" (cells and neurotoxic molecules from the peripheral circulation that enter the CSF) can perturb the normal environment of the CNS and are thought to play a major role in many diseases affecting the nervous system. See Caughey, B. and P.T. 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 P.T. 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, they share similar therapeutic mechanisms from a medical device perspective.

[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 beta-amyloid protein (Aβ) plaques from the brain, for example, in Alzheimer's disease (AD). These approaches include both active and passive immunization techniques. Active immunization approaches utilize various routes of administration, types of adjuvants, modified Aβ epitopes, and / or immunogenic Aβ conjugates. See Morgan, D., D. M. Diamond et al. (2000) Nature 408(6815):982-5. Passive immunization approaches involve monoclonal antibodies or specific antibody fragments (Fab) directed against specific Aβ epitopes. See Monsonego, A. and H. L. Weiner (2003) Science 302(5646):834-8. Plaque clearance as a result of immunotherapy may depend on multiple mechanisms. One theory involves direct interaction of antibodies or Fab fragments with 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 of soluble Aβ oligomers along a concentration gradient between the brain, CSF, and plasma. See Roberson, E. D., and L. Mucke (2006) Science 314 (5800):781-4. There is significant data from animal studies supporting both mechanisms, showing that substantial reductions in Aβ burden in transgenic mouse models were accompanied by improvements in memory impairment. 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 improvement of cognitive impairment, led to human clinical trials. Unfortunately, human patients actively immunized with Aβ immunogens developed signs 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, potentially negating the therapeutic effect of passive immunotherapy and potentially resulting in a harmful 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] A primary concern regarding both active and passive immunization lies in the pro-inflammatory consequences following immunization, which may lead to microglial hyperactivation. In addition to multiple inflammatory pathways thought to be involved in AD, certain inflammatory pathways are specifically activated following microglial stimulation, including the release of proteases and cytokines, as well as the activation of oxidative breakdown during Aβ clearance, which may exacerbate brain inflammation and AD-related neurodegeneration. In addition to inflammation, concerns exist regarding immune tolerance and the production of autoantibodies, and the inability to reverse treatment once administered. Furthermore, the redistribution of soluble Aβ oligomers along the brain-CSF-plasma concentration gradient remains unclear, as does the redistribution of Aβ oligomers, whether they are degraded in plasma or absorbed by specific organs. Addressing these concerns requires therapies that block antibody entry into 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, along with detailed rationale, are provided below for numerous neurological disorders for which there are currently limited or ineffective therapies.

[0063] It would be desirable to provide improved and alternative methods, systems, and 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 (such as red blood cells and their breakdown products in cerebral vasospasm, T and B cells in MS, and autoantibodies in GBS). Recent advances in nanotechnology and ultrafiltration now allow removal of agents on the nanometer scale, rather than micrometers, which represents a nearly 1000-fold improvement over previous systems in targeted filtration. Previous size-based filtration methods were limited to 0.2 micron filters, allowing the majority of smaller, toxic molecules to pass directly through the filter and return to the patient.

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

[0065] Third, it has been shown that temperature regulation 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 rapid processing of large volumes of CSF while minimizing the impact on the pressure and volume inherent within the cranial / spinal cavity.

[0066] Purification (or compound removal) schemes can be tailored to specific diseases or groups of diseases based on numerous characteristics, including size, affinity, biochemical characteristics, and / or temperature, but more specifically, they 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 for passive flow but also include active pumping mechanisms that generate transient or continuous flow, thereby ensuring that inflow and outflow are relatively equal to each other. Additionally, numerous 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, and transmembrane pressure sensors. Pressure sensors are also available to continuously record, maintain, and adjust intracranial and / or intraspinal pressure. Programmable control of the collection, production, and overflow drain 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 immediate medical attention and investigation of the system. A given volume of CSF is outside the patient's body at any given time, which is less than the amount that causes spinal headaches or symptoms associated with excessive drainage.

[0067] Therefore, CSF purification / conditioning systems offer dual-lumen / multi-lumen catheter designs. Flow studies have shown that dual-lumen or multi-lumen catheters with inflow and outflow ports separated by an appropriate distance are useful for creating and maintaining dynamic circulation and efficient mixing / exchange of CSF. Given the normal variations in patient anatomy, such distances may vary from individual to individual. Therefore, systems that allow for variation in this distance in situ or prior to application (i.e., implantation) offer further performance improvements, as such systems can be applied across populations. The flow dynamics created using such systems are dramatically different from single-lumen systems or systems with closely spaced inflow and outflow points (Figure 7). Dye studies clearly demonstrate that the present system, incorporating a dual- or multi-lumen design and catheters with spaced infusion and effluent, allows for greater 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 CSF volume in a shorter period of time (Figure 8A). The system design has a dramatic effect on CSF physiology and flow. In the present dual-lumen system, the distance between 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 significantly increased turnover and access to the basal cisterns, ventricles, cranial, and spinal subarachnoid CSF compared to cases previously described elsewhere in the literature. The greater efficiency of targeted compound removal results from reduced reprocessing of the same fluid (Figure 8C).

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

[0069] Parallel or sequential processing of removal and return streams using the multi-lumen system of the present invention offers several advantages over single-lumen systems, which 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, requiring less human or manual intervention and providing better sterility control. Furthermore, continuous flow processing is not limited by volumetric limitations on throughput; a wide range of flow rates and volume exchanges can also be achieved (Figure 9). The only limitation is the dead-space volume of the tubing, especially in the case of partially external systems.

[0070] Lumen shape 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-lumen / multi-lumen catheter systems described herein include multiple designs, including, but not limited to, combinations of circular, oval, square, etc., in various sizes and orientations to avoid catheter clogging. The combination of transient and / or continuous flow helps maintain lumen patency and significantly reduces the risk of clogging associated with current systems. Dual-lumen or multi-lumen systems also allow for rapid clearing of clogs through flow reversal and intermittent flow reversal by a pumping system. Dual-lumen systems also offer the added benefit of increasing the duration of a particular flow direction by moving clogging agents further 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 directed outflow to create swirl or turbulence, thereby enhancing mixing (FIG. 11).

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

[0073] Portions 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 radiopaque marker for precise localization and confirmation of the location of the catheter tip in the cranial or spinal CSF space. The radiopaque marker can then be visualized using plain x-ray or computed tomography. A variety of other methods can be utilized to confirm accurate catheter placement and placement. 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 containing 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 CSF infection is significant and includes meningitis, encephalitis, and even death. Numerous safety measures can be incorporated into the present invention to minimize and / or eliminate the potential risk of patient infection. First, the proximal end of the catheter can be inserted at various distances from the entry site to minimize the risk of organisms migrating back through the skin surface entry site. Second, a nurse can meticulously cleanse the catheter access site daily, or the patient can be instructed to do so. Third, antibiotics can be administered to the patient immediately prior to catheter placement, during the period the catheter is in place during CSF processing, and immediately after removal to further reduce the risk of infection. Fourth, the catheter system itself can be impregnated with an optimal specific antibiotic. Fifth, specific metals capable of generating a temporarily charged surface can be incorporated. Such metals have generally been shown to inhibit bacterial ingrowth and the development of catheter infections. Sixth, optimal antibiotics can be delivered into the CSF at specific times before, during, or after CSF processing to further eliminate the risk of bacterial seeding or infection. Finally, antibiotic cuffs 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, incorporating specific shape memory alloys into catheters for use in the CSF space (e.g., in one of the lumens in Figure 9B) can also be an additional strategy to prevent kinking, maintain their shape, and allow maximum access to the CSF space. Nickel titanium is a shape memory alloy, commonly referred to as nitinol. Above its transformation temperature, it is superelastic and can withstand large amounts of deformation. Below its transformation temperature, it exhibits a shape memory effect. Once deformed, it retains its shape until heated above its transformation temperature, at which point it returns to its original shape. Nitinol is typically composed of approximately 55% nickel by weight, and small changes in composition can significantly alter the alloy's transition temperature, making it suitable for many medical applications. In some embodiments, catheters incorporate nickel titanium into their manufacture. The superelasticity of nitinol allows such a catheter to easily enter through the cranial or spinal access pathway, while its shape memory allows it to return to its previous configuration once inside the CSF space. Nitinol's physical function is similar to that of biological muscle, contracting when activated. The contraction motion can be applied to any task requiring physical movement with low to moderate cyclic speeds. Given its small size, light weight, ease of use, and quiet operation, nitinol can also replace small motors or solenoids. Such a catheter system, internally adjustable and adaptable to access various regions of the cranial or spinal CSF space while minimizing the risk of kinking and catheter blockage, is an additional feature of the present invention.

[0077] In some embodiments, these systems incorporate conductive materials or heat exchange elements within portions of the catheter system (e.g., within one of the lumens in Figure 9B) that allow for rapid and direct changes in CSF space in the event of an injury requiring rapid temperature regulation. While the neuroprotective effects of significant hypothermia have long been recognized, the use of hypothermia for the treatment of neurological injury has often been abandoned due to management problems and severe side effects such as cardiac arrhythmias, chills, infections, and coagulation disorders. Over 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 allow 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 have significant beneficial effects on patients suffering from traumatic brain injury or spinal cord injury. In contrast, hyperthermia has been shown to have a markedly negative effect on CNS histopathology and outcome.

[0078] Such temperature-regulatable cooling catheters, specifically designed for the cranial or spinal CSF space, can be used independently or in conjunction with previously described extracorporeal cooling systems, providing 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 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, and regulate temperature.

[0079] The system allows for the connection of multiple different CSF inflow and outflow ports for CSF processing between any point in the CSF system, with overall inflow and outflow being relatively equal. The spatial locations of the inflow and outflow ports are sufficiently separated to allow CSF to flow throughout most or all of the CSF space. Custom-made cranial or spinal catheters can be introduced via multiple routes, including, but not limited to, single-ventricle insertion, dual-ventricle insertion, single-level spinal insertion, dual / multiple-level spinal insertion, and ventriculospinal insertion. In some embodiments, a first catheter is inserted into a ventricle or cervical vertebra, and a second catheter is inserted into a lumbar vertebra. Furthermore, any of the above systems may be configured to exchange CSF from any two points within the subarachnoid space. One example is a ventricular catheter with entry / exit sites communicating with the subarachnoid space covering the adjacent brain parenchyma.

[0080] The system allows for the active movement of large volumes of CSF over extended periods of time, without the need for CSF removal or diversion from the human body. Various inlet and outlet sites within the custom-designed catheter allow the system to generate active CSF flow in addition to the normal passive CSF flow. Active CSF movement can be generated in a number of ways, including, but not limited to, electrically driven pumps for active CSF withdrawal and return. Furthermore, pumping systems may have a variety of mechanisms to facilitate the requirement for relatively equal inflow and outflow. Examples of suitable pumps include rotary pumps, syringe-driven pumps, positive displacement pumps, peristaltic pumps, piston pumps, pneumatic pumps, bellows, electromagnetic pumps, magnetostrictive pumps, hydraulic pumps, and others. The pump may be a single device with bidirectional functionality, or two unidirectional pumps in communication with each other. Several pumping mechanisms are 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, Archimedes pumps).

[0081] In some embodiments, these systems provide a customizable conditioning system based on the specific disease being 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, immunotherapeutic applications, immunomodulatory, enzymatic digestion, and the like. In addition to various neurochemical filtration approaches, other filtration systems based on electromechanical principles may also be utilized, including radiofrequency, electromagnetic, sonic, piezoelectric, electrostatic, atomic force, and ultrasonic filtration. Other features can be added to filtration systems, including differential centrifugal forces to aid in the rapid separation of items of interest, such as ultrafiltration products, proteins, cells, and the like.

[0082] In some embodiments, cartridge-based schemes or combinations of the aforementioned purification-based schemes can be utilized for rapid changeover. For example, systems combining size-, antibody-, and charge-based approaches using single or multiple cartridges for purification are envisioned, so that when it is time to replace a purification filter, antibody, etc., replacement can be accomplished with an easy-to-use, rapid-change system. The conditioning system or chromatographic cartridge (e.g., biospecific interaction, ion exchange, 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 continuously sampled 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 noninvasively record, maintain, and 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 cerebrospinal fluid in 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. In the case of a spinal catheter, a cannula is placed at a 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 patient's lumbar vertebrae, 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 supine, sitting, 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 natural passive flow augmentation using 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 causes spinal headache or symptoms of overdrainage (approximately 40 ml). The location of the catheter can vary, but can include central ventricular insertion, dual ventricular insertion, single-level spinal insertion, two / multiple-level spinal insertion, and single-lumen, multi-lumen, or combination catheters placed via the ventriculospinal route.

[0085] One example is the use of a single-level spinal insertion, with the catheter inserted into the lumbar space and fed into the cranial cavity, with the tip of the catheter in the cervical region. 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 region. In another embodiment, both the inflow and outflow ports are in the cranial space, e.g., one port in the first ventricle and the second port 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-, biospecific-, and / or temperature-mediated mechanisms, as described above. In performing the conditioning step, the removed or collected CSF is contacted with one or more substrates containing chromatographic, electrochemical, or electromechanical selection agents.

[0088] These methods provide customizable conditioning schemes based on the specific disease process being 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, for example, based on A-domain scaffolds, also find use. In addition to various chromatographic approaches, electromechanical-based filtration systems also find use, including radiofrequency, electromagnetic, sonic, piezoelectric, electrostatic, atomic force, and ultrasonic filtration. 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 selection criteria based on size, biospecificity, and charge. 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, with a common feature being the disruption of the neuroimmune axis or weakness in the blood-brain barrier, resulting in B-cell, T-cell, and humoral and cell-mediated immune responses. In both cases, normal neuronal structures fall victim to a wide range of neuroinflammatory components and reactive oxidative stress proteins. The present invention allows for the targeted removal of inflammatory cells and proteins and the elimination and / or neutralization of oxidative stress proteins.

[0091] In the case of immunotherapy, current 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, eliminating any risk of initiating a systemic immune response against the self. Furthermore, this eliminates the risk of autoantibodies to systemically delivered immunotherapy, which can have devastating effects and high mortality rates in a subset of patients. A cartridge-based scheme allows for more rapid changeover 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 antibodies. Furthermore, the eluted compounds then become purified human proteins that can be used as "neurologic" agents. For example, in the case of Alzheimer's disease, purified Aβ or tau components can then be released and used for a variety of other commercial or research studies of 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 them to generate CSF banks for specific disease processes.

[0093] The conditioned endogenous CSF is then returned to a location different from the location from which it was withdrawn, returning it to 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 infusion to allow mixing of conditioned and unconditioned CSF throughout most of the CSF space. For example, at least about 50%, 60%, 70%, 80%, or 90% of the conditioned and unconditioned CSF in the CSF space can be mixed. The inflow and outflow ports are typically 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 spine), 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 ventricle embodiment). Depending on the design of the system, the quantitative distance between the inflow and outflow ports can 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 catheter's outflow lumen promote turbulent mixing after the return of conditioned CSF. For example, the distal portion of the outflow lumen can be configured as a single or dual helical conformation, contain multiple exit ports (i.e., side holes or ports), have a textured surface (e.g., bumps, ridges, etc.) that induces turbulence, or 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 and return steps can be performed simultaneously. This allows for a closed system and continuous processing or conditioning of the CSF, an advantage described herein. Overall, the inflow and outflow rates can be equal or substantially equal. As described above for these systems, 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 present method also contemplates the delivery of therapeutic agents via a return cycle. That is, after a given volume has passed through a specific purification scheme of interest, 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 the many systemic side effects 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. Various 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 enables the combined removal of specific toxins and delivery of 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, the 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 the abnormal accumulation of amyloid plaques and neurofibrillary tangles. Plaque formation is thought to result, in part, from the failure of beta-amyloid protein (Aβ) clearance. APP (amyloid precursor protein) generates various forms of amyloid-β through 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 the degeneration of neuronal axons and dendrites and the production of neurofibrillary tangles. The 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 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 effectiveness 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 treatment of amyloid and tau proteins by CSF and the neutralization of reactive oxidative species are both symptomatic and disease-modifying treatments, 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 the disease process from multiple different perspectives based on current understanding of pathogenesis.It may also be safer, as it carries a lower risk of liver damage and brain inflammation compared to current pharmacological therapy and immunotherapy, respectively.

[0099] Thus, the present 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 systems described herein. These methods include removing CSF from a 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, wherein the removing and returning steps are 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, a size-exclusion column, or both.

[0100] In another embodiment, these methods include introducing a catheter device into the CSF space of the patient's spinal cord through an access site in the spinal cord; advancing the catheter device through the CSF space of the spinal cord and into the skull toward the brain so that distal and proximal ports on the catheter device are positioned within the CSF space and are spaced a preselected distance apart or adjusted to an appropriate distance; withdrawing CSF through one of the ports; removing at least one of Aβ protein or tau protein or inflammatory mediators from the withdrawn CSF, thereby conditioning the CSF; and returning the conditioned CSF through the other of the ports, thereby alleviating or reducing symptoms 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) contribute to 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 symptomatic 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, S.B., and A. Bjorklund (1999) Nature 399 (6738 Suppl):A32-9; Dawson, T.M., and V.L. Dawson (2003) Science 302 (5646):819-22; and DeKosky, S.T., and K. Marek (2003) Science 302 (5646):830-4. Therapies that halt degeneration by removing free radicals and neurotoxic species are needed. See Shoulson, I. (1998) Science 282 (5391):1072-4. CSF filtration fulfills this unmet medical need and may represent a disease-modifying mechanism for the treatment of new PD.

[0102] Thus, the present methods alleviate or reduce the symptoms of Parkinson's disease by reducing or eliminating the presence of alpha-synuclein fibrils and / or oligomers in CSF using the systems described herein. 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, wherein the removing and returning steps are performed simultaneously during at least a portion of the treatment. In some embodiments, alpha-synuclein fibrils and oligomers are removed from the 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-wise through the CSF space of the spinal cord toward the brain so 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 the 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 the ports, thereby alleviating or reducing the 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 over a long period of time. See Rowland, LP (1995) Proc Natl Acad Sci USA 92(5):1251-3. Increased levels of neurofilament proteins and antibodies against GM1-ganglioside, AGM1-ganglioside, and sulfatides were found in 20%, 15%, and 8% of CSF samples from 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 the brain and muscles. 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 CSF would lower excessively high glutamate levels in the CSF and reduce oxidative species, thereby extending motor neuron lifespan and removing autoimmune antibodies and reactive oxidative species from the CSF without significant side effects such as liver damage.

[0105] Thus, the present methods 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), glutamate, neurofilamentous proteins, and anti-GM1 ganglioside antibodies in CSF using the systems described herein. These methods include removing CSF from a patient as described herein; removing at least one of insoluble superoxide dismutase-1 (SOD1), glutamate, neurofilamentous proteins, and anti-GM1 ganglioside antibodies or other inflammatory mediators 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, insoluble superoxide dismutase-1 (SOD1), glutamate, neurofilamentous proteins, anti-GM1 ganglioside antibodies, or other inflammatory mediators are removed from 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, these methods include introducing a catheter device into the CSF space of the patient's spinal cord through an access site in the spinal cord; advancing the catheter device through the CSF space of the spinal cord toward the brain so 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 the ports; removing at least one of insoluble superoxide dismutase-1 (SOD1), glutamate, neurofilamentous proteins, anti-GM1 ganglioside antibodies, or other inflammatory mediators from the withdrawn CSF, thereby conditioning the CSF; and returning the conditioned CSF through the other port, 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 lumen diameter of cerebral blood vessels thought to be due to blood in the subarachnoid space (e.g., after ruptured cerebral aneurysm, subarachnoid hemorrhage (SAH), craniocerebral trauma, bacterial meningitis, or after surgery in the sellar / parasellar region). 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 has a therapeutic effect through early, direct removal of clots, red blood cells, platelets, and the downstream cascade involving oxyhemoglobin and endothelin that leads to vasospasm.

[0108] Thus, the present methods 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 using the systems described herein. These methods include removing CSF from a 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, wherein the removing and returning steps are performed simultaneously during at least a portion of the treatment. In some embodiments, 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 an access site in the spinal cord; advancing the catheter device through the CSF space of the spinal cord toward the brain so 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 the 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 the 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 due to multiple causes: HSV (herpes simplex virus), Lyme disease, syphilis, bacterial infection, 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):140-147. Current therapies (adrenal steroids to reduce brain swelling and NSAIDs to reduce fever) do not target the cause of encephalitis. sTNF-R levels (reflecting the biological activity of TNF-alpha, a key 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 assist 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 present 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 a 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, wherein the removing and returning steps are 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 an access site in the spinal cord; advancing the catheter device through the CSF space of the spinal cord toward the brain so 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 the 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 port, thereby alleviating or reducing the symptoms of encephalitis.

[0113] Further embodiments for treating encephalitis are as discussed above and herein. vi. Guillain-Barré Syndrome (GBS) Guillain-Barré 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 and is accompanied by prominent lymphocytic infiltration of peripheral nerves and macrophage invasion of myelin and Schwann cells. Activated complement, found in the cerebrospinal fluid of Guillain-Barré 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 for severely paralyzed patients requiring 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 unable to walk independently. Results of international randomized trials have shown comparable efficacy between 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-Barré patients treated with CSF filtration indicate that this treatment is a safe and effective procedure. CSF filtration and plasma exchange are at least equally effective, 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, endotoxin, and cells). See Wollinsky, KH, PJ Hulser et al. (2001) Neurology 57(5):774-80. Thus, studies indicate that CSF filtration 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 present methods alleviate or reduce symptoms of Guillain-Barré syndrome (GBS) by reducing or eliminating the presence 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 in the CSF 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 endotoxin 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, 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 so 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 the ports; 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 withdrawn CSF, thereby conditioning the CSF; and returning the conditioned CSF through the other port, thereby alleviating or reducing symptoms of Guillain-Barré 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 its 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 MS plaques, which are areas of demyelination in 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 primarily localized around the plaques. B lymphocyte clones accumulate in the CSF of patients with MS and other neurological disorders. Anti-myelin-oligodendrocyte glycoprotein antibodies were detected in the CSF of seven patients with MS, compared with two patients with other neurological disorders and one patient with tension headache. See Hohlfeld, R. and H. Wekerle (2004) Proc Natl Acad Sci USA vol. 101, no. 2: 14599-606. Increased numbers of CD4+ T helper cells can be found in the CSF during early exacerbations. Osteopontin has been found to increase in patients' plasma before and during relapses, exacerbating autoimmune relapses and causing severe progression of the myelinating disease. See Hohlfeld, R. and H. Wekerle (2004) Proc Natl Acad Sci USA vol. 101, no. 2: 14599-606. Current therapies are limited and often ineffective and include steroids, interferon beta therapy, monoclonal antibody treatment, and global immunosuppression mediated by peptide fragments that mimic myelin proteins. Purification of CSF has the advantage of depleting cell populations that mitigate the effects of MS exacerbations by: 1) removing autoreactive CD4+ and CD8+ T cells, 2) reducing levels of pro-inflammatory 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 prevent the lesions that characterize disease progression.By limiting this depletion to the CSF, the present systems and methods address these problems without many of the complications associated with steroid treatment or systemic immunosuppression.

[0117] Thus, the present methods 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, and interferon-γ using the systems described herein. 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, and 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, and 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 involve introducing a catheter device into the CSF space of the patient's spinal cord through an access site in the spinal cord; advancing the catheter device through the CSF space of the spinal cord toward the brain so 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 the 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, and interferon-γ from the withdrawn CSF, thereby conditioning the CSF; and returning the conditioned CSF through the other of the 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 A stroke occurs when a blood clot blocks an artery or a blood vessel ruptures, 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 is elevated in patients with transient ischemic attacks and complete strokes. See McCulloch, J. and D. Dewar (2001) Proc Natl Acad Sci US A 98(20):10989-91. High cerebrospinal fluid enolase has consistently been associated with poor prognosis. Endothelin-1 (ET-1), a highly potent endogenous vasoactive peptide, exerts a sustained vasoconstrictive effect on cerebral blood vessels. See Mascia, L., L. Fedorko et al. (2001) Stroke 32(5):1185-90; and Kessler, I.M., Y.G. Pacheco et al. (2005) Surg Neurol 64(Suppl. 1):S1:2-5; discussion S1:5. Elevated plasma ET-1 levels have been reported on days 1 to 3 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<0.001). See Mascia, L., L. Fedorko et al. (2001) Stroke 32(5):1185-90; and Kessler, I.M., Y.G. Pacheco et al. (2005) Surg Neurol 64(Suppl. 1):S1:2-5; discussion S1:5. Current management of stroke is ineffective and involves symptomatic treatment (surgery, inpatient care, and rehabilitation) with the risk of cerebral hemorrhage (cerebral angioplasty and the use of tissue plasminogen activator (tPA) to dissolve acute blood clots in blood vessels). Similarly, traumatic brain injury (TBI) or spinal cord injury (SCI) occurs when sudden trauma affects the brain or spinal cord, such as after a fall, traffic accident, or assault. Current treatment for TBI and SCI focuses on increasing independence in daily activities and rehabilitation (i.e., individual therapy).Moderate hypothermia is thought to limit deleterious metabolic processes that can exacerbate injury. Treatment of 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, which is expected to be more rapid and effective than whole-body cooling. Whole-body cooling is limited by the risk of chills and severe cardiac arrhythmias.

[0120] Thus, the present methods use the systems described herein to alleviate or reduce symptoms of stroke, traumatic brain injury (TBI), or spinal cord injury (SCI) by reducing or eliminating the presence of one or more of endothelin, enolase, or other inflammatory mediators in the CSF. These methods include removing CSF from a patient as described herein; removing at least one of endothelin and enolase 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, endothelin, 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, 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-wise through the CSF space of the spinal cord toward the brain so 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 the 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 port, thereby alleviating or reducing symptoms of stroke, TBI, or 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 variations 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

[Claim 1] An apparatus, system, or method as set forth in the drawings.

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