EPILEPTIC SEIZURE THERAPIES COMPRISING PARTIAL REDUCTION OR COOLING OF BLOOD FLOW TO BRAIN REGIONS

Abstract

We report a method of treating an epileptic seizure in a patient, comprising: detecting said epileptic seizure, based on body data from said patient; and reducing a flow of blood to a brain of said patient in response to said detected seizure; wherein said reducing is effected by at least one of: applying a pressure, applying a cooling, or administering a vasoconstrictive agent to a vessel supplying blood to at least a portion of the brain. We also report a medical device system configured to implement the method. We also report a non-transitory computer readable program storage unit encoded with instructions that, when executed by a computer, perform the method.

Description

FIELD OF THE INVENTION

This disclosure relates to medical device systems and methods capable of treating epileptic seizures.

SUMMARY OF THE INVENTION

In some embodiments, the present disclosure relates to a method of treating an epileptic seizure in a patient, comprising detecting the epileptic seizure based on body data from the patient; and reducing a flow of blood to a brain of the patient in response to the detected seizure; wherein the reducing is effected by at least one of: applying a pressure, applying a cooling, or administering a vasoconstrictive agent to a vessel supplying blood to at least a portion of the brain. In one embodiment, the vessel supplies blood to one or more of a cortical or sub-cortical anterior structure, posterior structure, lateral structure, or mesial structure of the brain.

In some embodiments, the present disclosure relates to a method of treating an epileptic seizure in a patient, comprising: detecting the epileptic seizure, based on body data from the patient; and cooling the blood flowing to the brain of the patient in response to the detected seizure; wherein the cooling is applied to a carotid artery or a branch thereof.

In some embodiments, the present disclosure relates to a method of treating an epileptic seizure in a patient, comprising: detecting the epileptic seizure, based on body data from the patient; and reducing the flow of blood to the brain of the patient in response to the detected seizure by reducing the flow of blood in a carotid artery or a branch thereof or in a vertebral artery or a branch thereof. The flow of blood may be reduced in one embodiment by applying a pressure to a carotid or a vertebral artery, and in another embodiment by constricting the carotid or vertebral artery.

In other embodiments, the present disclosure relates to a medical device system, comprising at least one of a pressure device configured to apply pressure to at least a portion of a vessel supplying blood to the brain of a patient, a cooling device configured to cool at least a portion of a vessel supplying blood to the brain of the patient, or a vasoconstrictive agent device configured to administer a vasoconstrictive agent to at least a portion of a vessel supplying blood to the brain of the patient; and a medical device, comprising a controller; an epileptic seizure detection module configured to detect an occurrence of an epileptic seizure based on body data from a patient; and a therapy device selected from a pressure signal generator configured to apply the pressure using the pressure device, a cooling signal generator configured to apply the cooling using the cooling device, or a vasoconstrictive signal generator configured to apply the vasoconstrictive agent using the vasoconstrictive agent device. In one embodiment, the vessel supplies blood to one or more of an anterior structure, posterior structure, lateral structure, or mesial structure of the brain.

In some embodiments, the present disclosure relates to a non-transitory computer readable program storage unit encoded with instructions that, when executed by a computer, perform a method as described above.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure may be understood by reference to the following description taken in conjunction with the accompanying drawings, in which like reference numerals identify like elements, and in which:

FIG. 1 shows a schematic diagram of a medical device system, in accordance with some embodiments of the present disclosure;

FIG. 2A shows a schematic diagram of an implanted medical device system, in accordance with some embodiments of the present disclosure;

FIG. 2B shows a schematic diagram of an implanted medical device system, in accordance with some embodiments of the present disclosure;

FIG. 2C shows a schematic diagram of an implanted medical device system, in accordance with some embodiments of the present disclosure;

FIG. 3 shows a flowchart depiction of a method, according to some embodiments of the present disclosure;

FIG. 4 shows a flowchart depiction of a method, according to some embodiments of the present disclosure;

FIG. 5 shows a flowchart depiction of a method, according to some embodiments of the present disclosure;

FIG. 6 summarizes the regulation of cortical microvessels from cells located in subcortical areas and within the cerebral cortex, according to some embodiments of the present disclosure; and

FIG. 7 presents astrocyte influences on neuronal energy supply, according to some embodiments of the present disclosure.

While the disclosure is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and are herein described in detail. It should be understood, however, that the description herein of specific embodiments is not intended to limit the disclosure to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the disclosure as defined by the appended claims.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

Illustrative embodiments of the disclosure are described herein. For clarity, not all features of an actual implementation are described. In the development of any actual embodiment, numerous implementation-specific decisions must be made to achieve design-specific goals, which will vary from one implementation to another. Such a development effort, while possibly complex and time-consuming, would nevertheless be a routine undertaking for persons of ordinary skill in the art having the benefit of this disclosure.

The word “or,” when used herein, has an inclusive meaning (“and/or”), unless an exclusive meaning (analogous to the logical concept “xor”).

Embodiments disclosed herein provide for reducing the flow of blood to the brain and/or reducing the blood's temperature supplying an epileptogenic network in response to detecting a seizure. Upon detecting a seizure based upon body data of a patient, blood flow to the patient's brain (or to an anterior structure, posterior structure, lateral structure, or mesial structure thereof) may be reduced and/or the blood's temperature lowered. Without being bound by theory, reducing the flow of blood to the brain, or cooling blood flowing to the brain, during a seizure may benefit the patient by terminating the seizure, reducing its severity, reducing the post-ictal period associated with the seizure, and/or exerting a neuroprotective effect.

Epileptic seizures markedly increase metabolic energy consumption which can be sustained only if the quantity and rate of delivery of energy substrates such as glucose match the demand. Blood supply to the epileptogenic zone increases by several-fold at or even before the onset of paroxysmal electrical activity. This marked increase in the availability of energy substrates sustains the paroxysmal (abnormal) electrical activity. Reduction in the delivery of energy substrates carried by arterial blood to a level below that required to maintain epileptic electrical activity may lead to its cessation. Such a reduction may be brought about by constricting the diameter of the arterial vessel. However, such constriction must be carefully titrated to avoid ischemic or hypoxic injury to non-epileptogenic tissue and/or to prevent the occurrence of serious or intolerable side effects.

Lowering the temperature of brain tissue to the epileptogenic network is known to block or abate epileptic seizures due to decreases in cerebral blood flow and in the cerebral metabolic rate CMRO₂. While direct cooling (by embedding cooling elements/probes into the epileptogenic tissue) is the state-of-the art approach, cooling of blood supplying the epileptogenic network may also be effective and would have certain advantages over the conventional approach. One or more of a plurality of steps may be taken to reduce the flow of blood to the patient's brain, e.g., applying pressure, cooling, or administering a vasoconstrictive agent to a vessel supplying blood to a portion of the brain. In one embodiment, applying pressure to the vessel comprises constricting the vessel to reduce the flow of blood in the vessel. The vessel may supply blood to one or more of an anterior brain structure, a posterior brain structure, a deep brain structure, or a mesial brain structure.

In some embodiments, the present disclosure relates to a method of treating an epileptic seizure in a patient, comprising detecting the epileptic seizure based on body data from the patient; and reducing a flow of blood to a brain of the patient in response to the detected seizure; wherein the reducing is effected by constricting a vessel at least by one of: applying a pressure, cooling, or administering a vasoconstrictive agent to a vessel supplying blood to at least a portion (e.g., a “hub”) of an epileptogenic brain network. Though not to be bound by theory, such reducing may reduce, delay, prevent, or otherwise control seizure spread. For more information on control of seizure spread, see, e.g., U.S. patent application Ser. No. 13/449,166, filed Apr. 17, 2012, which is hereby incorporated herein by reference.

In further embodiments, constricting the vessel may be by applying a pressure, administering a vasoconstrictive agent, or both.

In some embodiments, the present disclosure relates to a method of treating an epileptic seizure in a patient, comprising: detecting the epileptic seizure, based on body data from the patient; and cooling the blood flowing to the brain of the patient in response to the detected seizure; wherein the cooling is applied to a vessel supplying blood to at least a portion (e.g., a “node”) of an epileptogenic network.

FIG. 1 shows a schematic representation of a medical device system, according to some embodiments of the present disclosure. The medical device system 100 may comprise a medical device 200, sensor(s) 212, and lead(s) 211 coupling the sensor(s) 212 to the medical device 200. In various embodiments, the medical device 200 may be implantable within a patient's body, may be external to a patient's body (e.g., the device may be part of a patch affixed to the patient's skin or may be in a housing suitable for wearing in a pocket, on a lanyard around the neck, etc.), or may be remote from the patient's body.

In one embodiment, sensor(s) 212 may each be configured to collect data from a patient from whom a pathological brain state, such as an epileptic seizure, may be detected.

More information regarding detecting an epileptic event from cardiac data, as well as information regarding measures of central tendency that can be determined from time series of body data, may be found in other patent applications assigned to Flint Hills Scientific, LLC or Cyberonics, Inc., such as, U.S. Ser. No. 12/770,562, filed Apr. 29, 2010; U.S. Ser. No. 12/771,727, filed Apr. 30, 2010; U.S. Ser. No. 12/771,783, filed Apr. 300, 2010; U.S. Ser. No. 12/884,051, filed Sep. 16, 2010; U.S. Ser. No. 13/554,367, filed Jul. 20, 2012; U.S. Ser. No. 13/554,694, filed Jul. 20, 2012; U.S. Ser. No. 13/559,116, filed Jul. 26, 2012; and U.S. Ser. No. 13/598,339, filed Aug. 29, 2012. Each of the patent applications identified in this paragraph is hereby incorporated herein by reference.

More information regarding detecting an epileptic event from multiple body data types, and examples of such body data types, may be found in other patent applications assigned to Flint Hills Scientific, LLC or Cyberonics, Inc., such as, U.S. Ser. No. 12/896,525, filed Oct. 1, 2010, now U.S. Pat. No. 8,337,404, issued Dec. 25, 2012; U.S. Ser. No. 13/098,262, filed Apr. 29, 2011; U.S. Ser. No. 13/288,886, filed Nov. 3, 2011; U.S. Ser. No. 13/554,367, filed Jul. 20, 2012; U.S. Ser. No. 13/554,694, filed Jul. 20, 2012; U.S. Ser. No. 13/559,116, filed Jul. 26, 2012; and U.S. Ser. No. 13/598,339, filed Aug. 29, 2012. Each of the patent applications identified in this paragraph is hereby incorporated herein by reference.

More information regarding the detection of abnormal brain activity, such as seizures, identifying brain locations susceptible to spread of the abnormal brain activity, and treating the susceptible brain locations may be found in other patent applications assigned to Flint Hills Scientific, LLC or Cyberonics, Inc., such as, U.S. Ser. No. 13/449,166, filed Apr. 17, 2012. Any patent application identified in this paragraph is hereby incorporated herein by reference.

More information regarding automated assessments of therapies may be found in other patent applications assigned to Flint Hills Scientific, LLC or Cyberonics, Inc., such as, U.S. Ser. No. 12/729,093, filed Mar. 22, 2010; U.S. Ser. No. 13/280,178, filed Oct. 24, 2011; U.S. Ser. No. 13/308,913, filed Dec. 1, 2011; and U.S. Ser. No. 13/472,365, filed May 15, 2012. Each of the patent applications identified in this paragraph is hereby incorporated herein by reference.

More information regarding the detection of brain or body activity using sensors implanted in proximity to the base of the skull may be found in other patent applications assigned to Flint Hills Scientific, LLC or Cyberonics, Inc., such as, U.S. Ser. No. 13/678,339, filed Nov. 15, 2012. Any patent application identified in this paragraph is hereby incorporated herein by reference.

Various components of the medical device 200, such as controller 210, processor 215, memory 217, power supply 230, communication unit 240, warning unit 292, second therapy unit 294, logging unit 296, and severity unit 298 have been described in other patent applications assigned to Flint Hills Scientific, LLC or Cyberonics, Inc., such as those incorporated by reference, supra.

The medical device system 100 may comprise at least one of a pressure device 110a configured to apply pressure to a vessel supplying blood to at least a portion of the brain of a patient, a cooling device 110b configured to cool at least a portion of a vessel supplying blood to at least a portion of the brain of the patient, or a vasoconstrictive agent device 110c configured to administer a vasoconstrictive agent to at least a portion of a vessel supplying blood to at least a portion of the brain of the patient. One or more devices 110a-110c may be referred to as a “first therapy device” or a “first therapy unit.” Restricting blood flow to a vessel supplying blood to epileptogenic networks or to those that facilitate seizure generation may enable blockage of seizure generation, termination of seizures (if generation was not suppressed), reduction of their severity (e.g., spread is prevented), and/or reduction of the duration or severity of the post-ictal period.

By “a vessel supplying blood to at least a portion of the brain” of a patient is meant any portion of the vasculature (regardless of caliber) supplying blood to or withdrawing blood from the brain of the patient. In some embodiments, the vessel supplies blood to an epileptogenic or pro-epileptogenic region of the brain. The right and left carotid and right and left vertebral arteries are the largest caliber vessels susceptible to therapeutic intervention (e.g., exogenous narrowing). The right and left jugular veins are the most distal and largest veins also amenable to intervention. The terms “anterior” and “posterior” regarding cerebral vasculature are relative to the Circle of Willis (e.g., the anterior cerebral, anterior communicating, posterior cerebral, and posterior communicating arteries).

The concept of anterior, posterior, lateral, or mesial structures, as applied in certain embodiments of the present disclosure, is based on the practice to refer to the carotid arteries and their entire vascular tree as the anterior circulation and the vertebral arteries as the posterior circulation. The terms lateral and mesial are applied to structures in the same lobe (e.g., temporal) that, while roughly at the same level in the anterior-posterior (A-P) plane in reference to an A-P fiducial point, are not supplied by the circulation that supplies other structures on the same A-P plane level, or that may receive blood from both the anterior and posterior circulation. For example, areas of the temporal neocortex (laterally placed) receive supply from a branch (middle cerebral) of the carotid artery, while those located mesially but at the same level in the A-P plane are either supplied by a branch of the vertebral artery (posterior cerebral) or by this branch and a branch (anterior choroidal) of the carotid artery.

Typically, the vessel of interest will be part of the arterial vasculature, such as a carotid artery, one of its branches (e.g., anterior choroidal; middle cerebral) or a vertebral artery, one of its branches (e.g., posterior cerebral) or sub-branches (e.g., anterior hippocampal). The choice of an arterial vessels depends on the location (right or left hemisphere); lobe (e.g., temporal); region with the lobe (e.g., mesial temporal), and the extent of brain tissue which it supplies with blood (e.g., how much of a hemisphere, lobe, region, or sub-region (e.g., hippocampus) it supplies). For example, if the epileptogenic network spans the dorsolateral frontal and parietal lobes, the ipsilateral carotid artery may be the therapeutic target. If hippocampus and amygdala are the seats of the epileptogenic network, the anterior choroidal (a branch of the carotid) and the posterior lateral choroidal artery (a branch of the posterior cerebral) may be cooled or constricted; these small vessels may be localized using 1.5 T or 3 T MRI.

In one embodiment, given the variability in vascular supply to mesial temporal structures, selection of vessels for therapeutic targeting may be based on high resolution imaging.

In some embodiments, the pressure device 110a may be a circumarterial cuff, such as is shown in FIG. 2A. Regardless of the structure of the pressure device 110a, it may be configured to apply a certain pressure to a vessel, and/or allow selection of various pressure settings, depending at least on the caliber of the vessel and/or the required reduction in blood flow through the cuff. Generally, it is desirable that the pressure applied to a vessel be sufficient to reversibly disrupt synaptic transmission in brain tissue supplied by the vessel without causing neuronal damage. Critical values of blood flow that lead to reversible blockage of synaptic transmission and hence neuronal function are between 15 and 18 ml/100 gm/minute. The threshold for membrane pump failure, and thus for loss of cellular integrity and irreversible neuronal damage, is approximately 10 ml/100 gm/minute. Because an epileptic seizure is a highly energy consuming event, selective blockage or abatement of paroxysmal electrical activity may be accomplished at blood flows above 18 ml/100 gm brain tissue/minute. (By “selective” is meant blockage or abatement of paroxysmal/abnormal activity without disruption of non-paroxysmal/physiological neuronal activity so as to not cause adverse effects). Partial reduction of blood supply may be sufficient to reduce blood flow to a level that will “starve” the seizure of oxygen and/or glucose, while allowing parts of the brain free of the seizure to function properly.

Different cellular functions, which require specific minimum levels of blood flow, are affected in these regions depending on the level of blood flow reduction. Certain functional perturbations occur once blood flow decreases below these thresholds. Critical values for loss of synaptic transmission, corresponding to loss of neuronal function, are between 15 and 18 ml/100 g per minute. The threshold for membrane pump failure, and thus for loss of cellular integrity, is approximately 10 ml/100 g per minute. The level of blood flow reduction for ion pump failure appears to be similar to that for energy failure. The presence of these two distinct thresholds implies that some regions in the perifocal area contain cells that are electrophysiologically quiescent but nonetheless viable. These regions constitute the ischemic penumbra, defined as areas with EEG quiescence and low extracellular K+. These thresholds were determined in experimental models using both primates and other higher vertebrates. Similar values have been reported in humans. While absolute values may vary somewhat depending on the species and anesthetic factors, the percent reduction from normal flow to these thresholds appears to be uniform and constant.

Flow reduction is one component that determines the severity of an ischemic insult, but the duration of flow reduction is also of paramount importance. The threshold for infarction in monkeys is approximately 12 ml/100 g per minute, but that the duration as well as the degree of blood flow reduction was important, since infarction developed only if blood flow was reduced to below 12 ml/100 g per minute for periods lasting 2 h or longer. Since the time course for irreversible damage in complete global ischemia models is much shorter-approximately 10 min—it is reasonable to suspect that areas with more profound blood flow reduction in focal ischemia have a shorter tolerance than areas with higher levels of blood flow.

The existence of two distinct thresholds suggests that some areas in the perifocal region contain cells that are electrically silent but nonetheless viable. These cells are the likely targets for prevention of ischemic injury, since they should be the most susceptible to therapeutic rescue. The ability to maintain a low extracellular potassium concentration in the perifocal region implies that sufficient energy stores remain to maintain near-normal electrochemical gradients, but the neuronal paralysis and reduced blood flow suggest that the penumbra is clearly at risk for further damage.

FIG. 6 summarizes the regulation of cortical microvessels from cells located in subcortical areas and within the cerebral cortex. The possibility that interneurons also induce the release of vasoactive molecules from astrocytes is not included for clarity purposes. The known or suggested vasoactive mediators and the vascular receptors on which neuronal or astroglial (PGE2 and 20-HETE) signaling molecules are believed to act to induce dilatation or constriction are illustrated. Note that GABA has been shown to dilate, via GABAA receptors, pial vessels but not intracortical microvessels. M5, muscarinic receptors that mediate dilatation of cerebral microvessels; VAPC1, dilatory receptor for VIP in brain vessels; NPY1, NPY receptor mediating cerebral vasoconstriction; SSR2/4, somatostatin receptors on smooth muscle cells of cortical microvessels that can mediate contraction [4]; 5-HT1B, contractile receptor for 5-HT, but note that a dilatory response mediated by the same receptor has also been reported [11]; EP4, dilatory receptors for PGE2 in brain vessels [7]; the cerebrovascular receptor for 20-HETE is still unknown. (Based on information in J Appl Physiol 2006; 100:1059-1064).

FIG. 7 presents astrocyte influences on neuronal energy supply. Perivascular astrocytes respond to neuronal input (activity) by supplying neurons with substrates for oxidative phosphorylation (lactate, glutamine (Gln)) and glutamate (Glu) replenishment (glutamine), and by signaling changes in local blood flow at the vascular level. Active neurons produce synaptic glutamate that can be taken up by astrocyte glutamate transporters (EAAT, excitatory amino acid transporter) or activate mGluRs. (1) EAAT activation drives electrogenic Na+ influx, activates Na+/K+ ATPases and stimulates glycolytic lactate generation. (2) mGluR activation also leads to glycolysis and lactate production, and neuronal activity drives astrocyte glycogenolysis (3) and eventual lactate formation. Lactate from these three sources is released to the extracellular space via monocarboxylate transporter I (MCT1) where it can be taken up by neuronal MCT2 and converted to pyruvate (Pyr) for entry into the TCA cycle (4). Glutamate taken up by astrocyte EAATs can also be converted to glutamine by glutamine synthetase (5). Glutamine can be released and taken up by neuronal amino acid transporters for re-synthesis of glutamate and/or γ-aminobutyric acid via the TCA cycle. For astrocyte changes in blood flow, mGluR activation causes increased Ca2+ levels (6), leading to phospholipase A2 (PLA2) activation, arachidonic acid (AA) formation (7) and vasoconstriction following 20-HETE production by cytochrome P450 ω-hydroxylate (8) and continuous prostaglandin E₂ (PGE₂) generation by cyclooxygenase (COX) (9). Vasodilation can result in hypoxic conditions from lactate-mediated inhibition of PGE₂ clearance by prostaglandin transporters (PGT) following PGE₂ diffusion to the vascular smooth muscle (10).

According to the general equation of flow, CBF can be described by the relationship between cerebral perfusion pressure (CPP) and cerebrovascular resistance (CVR): CBF=CPP/CVR.

Cerebral perfusion pressure is equal to mean arterial blood pressure (MABP) [where MABP=⅓(systolic pressure−diastolic pressure)+diastolic pressure] minus intracranial pressure and sagittal sinus pressure. In the absence of pathologic conditions, intracranial pressure and sagittal sinus pressure are negligible compared to systemic arterial pressure, and CPP is roughly equivalent to MABP. According to the previous equation, autoregulation must be mediated by changes in CVR. The Hagen-Poiseuille equation, which describes the flow of Newtonian fluids in rigid tubes, offers an approximation of the factors that govern CVR and suggests that resistance is inversely proportional to blood viscosity and proportional to the fourth power of the radius of the vessel. Thus, changes in the radius of cerebral blood vessels can produce marked alterations of CVR. A decrease in CPP produces dilation of the precapillary resistance vessels, whereas an increase produces constriction. Largely by variation in the degree of constriction of the cerebral resistance vessels, average hemispheric CBF is maintained at a fairly constant level, near 50 ml/100 g per minute in the adult human brain at rest.

$\mathrm{Strain}=\frac{\mathrm{Change}\mathrm{in}\mathrm{length}}{\mathrm{Initial}\mathrm{length}}=\frac{\mathrm{total}\Delta l}{l_o}$ $\mathrm{Tension}=\mathrm{Pressure}\times \frac{\mathrm{Radius}}{\mathrm{Wall}\mathrm{thickness}}$

Alternatively, in certain situations (e.g., low profusion pressure and low volume), causing vasodilation can also artificially decrease blood flow to brain by substantially lowering cerebral blood pressure to the point in which blood flow is vastly lowered or the delivery rate is decreased. Another alternative to decrease blood flow to the epileptogenic network is to divert the blood flow through a blood flow shunt to non-epileptogenic brain regions or other organs (e.g., a patient's legs).

Another benefit (in terms of decreasing the risk of stroke or ischemic injury) to partial reduction in blood flow relates to the Circle of Willis. The Circle of Willis is a circuit in the arterial vasculature of the brain which is activated upon drop in blood flow in one or more of its branches. As a result, the Circle of Willis will allow supplementation of blood to flow to regions normally served by a compromised portion of the arterial vasculature. In some embodiments, the pressure exerted on a vessel is below the activation level of the Circle of Willis.

In some embodiments, the pressure device 110a may be configured to apply the pressure to at least a portion of a posterior cerebral artery or a branch thereof.

FIG. 2A shows a schematic 150a of a pressure device 110a (in the depicted embodiment, a circumarterial cuff) after implantation to a portion 105 of a vessel supplying blood to at least a portion of the brain.

In some embodiments, the cooling device 110b may be a thermoelectric device (e.g., a Peltier cooler) or a refrigerant system. A thermoelectric device is shown in FIG. 2B. In addition to evaluating a thermoelectric device based upon a cooling capacity, consideration must be given to regional heating that occurs at the thermoelectric device. As the excess heat is removed from the blood, thus providing the chilling effect to the blood, the heat generated needs to be managed to prevent damage to the surrounding tissue.

Regardless of the structure of the cooling device 110b, it may be configured to cool the vessel to one temperature, or allow selection of one of multiple temperatures to which the vessel may be cooled. Generally, it is desirable for the amount of cooling applied to not decrease the blood flow below 18 ml/100 gm/min, in order to decrease the probability of causing adverse effects arising from blockage of synaptic transmission to non-epileptogenic tissue that may be supplied by the cooled arterial vessel. Because an epileptic seizure is a highly energy consuming event, a relatively low cooling may still be sufficient to reduce blood flow and decrease CMRO₂ to an extent that will “starve” the seizure of oxygen and/or glucose, while allowing parts of the brain free of the seizure to function properly.

Cooling brain tissue to temperatures between 18-21° C. generally abates seizures. To reach this or lower tissue temperatures through transmural cooling of arterial blood (e.g., by positioning the cooling element on an arterial wall), the temperature applied to an arterial wall must be lower than that of brain tissue. Arterial wall temperatures sufficient to lower brain tissue temperature to attain a therapeutic effect without causing damage to the blood vessel and brain tissue may be predetermined using computer models and simulation. (See Osorio et al, “Seizure control with thermal energy? Modeling of heat diffusivity in brain tissue and computer-based design of a prototype mini-cooler.” Epilepsy Behav. 2009 October; 16(2):203-11). Sensors (e.g., temperature, electrical, chemical, etc.) located within epileptogenic brain tissue and/or in the arterial wall, may be connected to a controller to regulate the magnitude and rate of cooling energy delivered to the wall. This servo-mechanism allows the setting of safe and effective temperatures. For example, if the artery wall temperature is reaching a level where tissue damage is likely to occur, the cooling device may be shut down. U.S. Pat. No. 7,204,833 entitled “Multi-modal system for detection and control of changes in brain state” issued Apr. 17, 2007 to Osorio et al., is incorporated herein by reference.

In some embodiments, the cooling device 110b may be configured to apply the cooling to at least a portion of the posterior cerebral artery, the branch thereof, a carotid artery, or a branch thereof.

In some embodiments, the cooling device 110b may be configured to cool flowing blood as it passes through the vessel supplying blood to at least a portion of the brain. The cooler blood may also have an anti-epileptic effect, as is known from prior considerations of cooling neural structures as a treatment for an epileptic seizure.

In some embodiments, the cooling device 110b may be implanted in a deep brain location and may be configured to cool one or more nearby blood vessels, leading to blood cooling.

FIG. 2B shows a schematic 150b of a cooling device 110b (in the depicted embodiment, a thermoelectric device) after implantation to a portion 105 of the brain.

The vasoconstrictive agent device 110c may be configured to deliver any appropriate vasoconstrictive agent (e.g., a vasoconstrictive drug such as those known in the art) to the vessel supplying blood to at least a portion of the brain. The vasoconstrictive agent device 110c may comprise a reservoir of the vasoconstrictive agent in a suitable solution, and appropriate pumping and metering apparatus. In some embodiments, the vasoconstrictive agent device 110c is configured to administer the vasoconstrictive agent to at least a portion of the posterior cerebral artery, the branch thereof, the carotid artery, or the branch thereof.

FIG. 2C shows a schematic 150c of a vasoconstrictive agent device 110c after implantation to a portion 105 of the vessel.

Returning to FIG. 1, the medical device 200 may comprise a controller 210 configured to direct the operations of other elements of the medical device 200 and the medical device system 100.

The medical device 200 may comprise an epileptic seizure detection module 250 configured to detect an occurrence of an epileptic seizure, based on body data from a patient, such as that collected via sensor(s) 212.

The medical device 200 may comprise at least one therapy device selected from a pressure signal generator 260a configured to signal the pressure device to apply the pressure, a cooling signal generator 260b configured to signal the cooling device to apply the cooling, or a vasoconstrictive signal generator 260c configured to signal the vasoconstrictive agent device to apply the vasoconstrictive agent. Regardless of the type of therapy, therapy device 260c-260c may be configured to receive an indication of an epileptic seizure from epileptic seizure detection module 250 and direct the application of pressure, cooling, or a vasoconstrictive agent to a vessel supplying blood to the brain via the corresponding device 110a-110c.

The medical device 200 may comprise one, two, or all three therapy devices 260a-260c and corresponding devices 110a-110c. In some embodiments, the medical device system 100 comprises pressure device 110a and the therapy device comprises the pressure signal generator 260a. In some embodiments, the medical device system 100 comprises cooling device 110b and the therapy device comprises cooling signal generator 260b. In some embodiments, the medical device system 100 comprises vasoconstrictive agent device 110c and the therapy device comprises vasoconstrictive signal generator 260c.

In some embodiments, the medical device 200 may further comprise a therapy control unit 270 configured to direct the therapy unit(s) 260a-260c to modify or stop the therapy in response to at least one directive based on one or more of a) a termination of the seizure (such as may be determined by epileptic seizure detection module 250); b) an increase in power in the 0-4 Hz frequency band in at least one brain region (such as may be determined by epileptic seizure detection module 250, therapy efficacy unit 293, adverse effect assessment unit 295, and/or severity unit 298); c) a decrease in power in all frequency bands in at least one brain region (such as may be determined by epileptic seizure detection module 250, therapy efficacy unit 293, adverse effect assessment unit 295, and/or severity unit 298); d) an impairment of a neurological function in at least one brain region (such as may be determined by therapy efficacy unit 293, adverse effect assessment unit 295, and/or severity unit 298); or e) lapse of a therapy time period. In case a), upon termination of the seizure, further therapy may no longer be needed. In cases b)-d), the therapy may lack efficacy and/or give rise to adverse effects, either or both of which may suggest the therapy is inappropriate and that another therapy may be delivered, either by another therapy device 260a-260c or a second therapy unit 294.

In one embodiment, the pressure applied to the vessel, the degree of cooling, and/or the quantity and rate of delivery of the vasocontrictive compound may be directly controlled by the blood flow rate distal to the site of therapy delivery. For example, if flow in the distal part of the vessel is approaching a critical value for tissue damage (<15 ml/100 gm/min) therapy delivery may be modified to prevent such an outcome.

When stopping therapy, the therapy device 260a-260c may be configured to gradually release the pressure, gradually rewarm, or gradually withdraw the vasoconstrictive agent. If the pressure may be released too quickly, the vessel rewarmed too rapidly, or the vasoconstrictive agent withdrawn too abruptly, these sudden actions may have an increased risk of rebound reentry of the patient into the seizure, or causing other undesired sequelae.

If included in the medical device 200, the second therapy unit 294 may provide any therapy known to the person of ordinary skill and/or disclosed by the Flint Hills and/or Cyberonics patent applications incorporated by reference. For example, the second therapy unit 294 may provide an anti-convulsive drug to the patient. In a particular embodiment, the second therapy unit 294 may be a vagus nerve stimulator, such as one commercially available from Cyberonics, Inc.

More generally, if one of the constrictive treatments and/or blood cooling described herein lacks efficacy, its parameters may be modified and/or one or more of the other treatments may replace it or be added. For example, all three treatments may be used simultaneously. In one embodiment, if all three treatments lack efficacy, electrical stimulation or anti-convulsive drugs may be used. In another embodiment, electrical stimulation or anti-convulsive drugs may be used in conjunction with one or more of the constrictive treatments described herein.

Although FIG. 1 shows units 250-298 as components of the medical device 200, in some embodiments, in some embodiments one or more of units 250-298 may be external to the medical device 200, such as in an implantable device, an external device, a remote device, etc. In still other embodiments, one or more of units 250-298 may be omitted.

FIG. 3 shows a flowchart representation of a method 300 of treating an epileptic seizure in a patient, comprising detecting the epileptic seizure, based on body data from the patient. In response, the method 300 may further comprise reducing a flow of blood to a brain of the patient in response to the detected seizure, wherein the reducing is effected by at least one of: applying at 320a a pressure, applying at 320b a cooling, or administering at 320c a vasoconstrictive agent to a vessel supplying blood to at least a portion of the brain, e.g., to reduce blood flow to at least a portion of the anterior, posterior, or mesial region of the brain. In some embodiments, the method 300 may include performing an action in response to the detected seizure (at 340). The action may comprise providing a second therapy (e.g., electrical therapy, chemical therapy, etc.) for attenuating the seizure and/or its effects. Further, the action may also comprise logging the seizure events (e.g., the date and time of occurrence, one or more seizure severity indices), the environmental circumstances associated with the seizure, and/or the actions taken in response to the seizure. Moreover, a warning may be provided in response to the seizure detection, wherein the warning may comprise providing a warning signal to the patient, to a healthcare personal, and/or to any designee. The warning may be audible, mechanical, and/or electronic (e.g., electrical signal, electronics communication, such as a telephone message, text messages, voicemail, email, and/or the like).

In some embodiments, the method 300 may further comprise identifying at 325 a brain region associated with the seizure. Identifying the brain region may comprise identifying an epileptogenic or pro-epileptogenic brain region. The vessel to which the pressure, cooling, or vasoconstrictive agent is applied may supply blood to the epileptogenic or pro-epileptogenic brain region.

In some embodiments, identifying a brain region associated with a seizure at 325 may be performed as part of an initial patient workup, e.g., through the use of electrophysiological (e.g., electroencephalography) or other appropriate techniques, a brain region that is epileptogenic or proepileptogenic in a major fraction of the patient's seizures may be identified. In light of this information, a brain structure or location providing blood flow to the brain region may selected for implantation of pressure, cooling, or vasoconstrictive agent devices 110a-110c prior to performance of elements 320a-320c. For example, if the majority of the patient's seizures have left occipital lobe origin, then a device 110a-110c may most desirably be implanted at a left posterior cerebral artery or of its branches.

In some embodiments, if one or more pressure devices 110a, one or more cooling devices 110b, and/or one or more vasoconstrictive agent devices 110c have been implanted, such that a plurality of devices have been implanted, then identifying a brain region associated with seizures at 325 may be performed during a seizure detection at 310, and the device of the plurality that is implanted at a most relevant location may be activated, e.g., if a first device is implanted at a left posterior cerebral artery and a second device implanted at the right posterior cerebral artery, and the patient's seizure is in the left occipital lobe, then the first device may be activated as the most likely device to reduce blood flow to the seizure location.

In some embodiments, the method 300 may further comprise modifying the therapy parameters (at 330) in response to at least one of a) a termination of the seizure; b) an increase in power in the 0-4 Hz frequency band in at least one brain region; c) a decrease in power in all frequency bands in at least one brain region; d) an impairment of a neurological function in at least one brain region; or e) lapse of a therapy time period. In other words, therapy may be stopped at 330 if the seizure terminates, the therapy lacks efficacy, the therapy gives rise to an adverse effect, and/or a dose of therapy is completed.

In some embodiments, modifying therapy at 330 may comprise at least gradually releasing the pressure, gradually rewarming, and/or gradually withdrawing the vasoconstrictive agent.

In some embodiments, the therapy parameters may be modified based on a detected change in the concentration of one or more energy substrates, one or more of certain ions (e.g., K⁺, H⁺), one or more tissue stress markers, or two or more thereof.

FIG. 4 presents a flowchart depiction of a method 400. The method 400 may comprise determining at 410 a brain location susceptible to emergence of an epileptic seizure. The method 400 may comprise determining at 420 a location for reducing blood flow and/or the metabolic rate in a selected epileptogenic or pro-epileptogenic region of the brain, to which blood flow and/or in which metabolic rate may be reduced to interrupt the epileptic seizure (or another unstable brain state). Thereafter, brain activity may be observed at 430. At various times, a determination may be made at 440 whether a pathological brain state (e.g., an epileptic seizure) has been detected. If a pathological brain state has not been detected, the brain is deemed to have normal function and flow may return to observing brain activity at 430. If a pathological brain state has been detected, then blood flow to and/or metabolic rate at the location determined at 420 may be reduced (at 450).

Reducing the blood flow at 450 may be performed by pressure, cooling, or a vasoconstrictive agent, as described supra.

FIG. 5 shows a flowchart depiction of a method 500 of treating an epileptic seizure in a patient, comprising detecting or anticipating at 510 an epileptic seizure, based on body data from the patient; and cooling and/or restricting at 520 blood flowing to a (pro)epileptogenic brain region of the patient in response to the detected/anticipated seizure; wherein the cooling is applied to at least one of a carotid artery, a branch thereof, a vertebral artery, or a branch thereof In some embodiments, this method may further comprise identifying at 525 an epileptogenic or pro-epileptogenic brain region, wherein the artery or the branch thereof supplies blood to the brain region. Identifying at 525 may be performed prior to implantation of a cooling device at the artery or branch thereof. Cooling may be applied by a thermoelectric device or a refrigerant system. Cooling may be stopped in response to one or more of the events described supra, and stopping the cooling may comprise gradually rewarming the blood.

Alternatively or in addition to vasoconstriction and/or blood cooling, in some embodiments, the supply of oxygen to an epileptogenic or pro-epileptogenic brain region can be reduced in one or more other ways. For example, small amounts of compounds that compete with oxygen for hemoglobin binding sites (e.g., CO, NO) may be introduced into the blood flowing towards the region to irreversibly displace O₂. It is expected that CO would be most suitable for cases with very small epileptogenic networks or preferably with hubs or nodes that when selectively targeted cause the seizure to abate or de-intensify. For another example, the pH of the patient's blood flowing towards the brain region may be changed to shift the hemoglobin dissociation curve to its lowest levels, i.e., to keep more oxygen bound to hemoglobin and deliver less to the brain region. However, such pH changes may alter the brain in ways that may foster seizure re-emergence. For yet another example, a non-metabolizable glucose (e.g., chemically-modified glucose) may be introduced into the blood supply to the epileptogenic or pro-epileptogenic brain region.

The methods depicted in FIGS. 3-5 and described above may be governed by instructions that are stored in a non-transitory computer readable storage medium and that are executed by, e.g., a processor 215 of the medical device 200. Each of the operations shown in FIGS. 3-5 may correspond to instructions stored in a non-transitory computer memory or computer readable storage medium. In various embodiments, the non-transitory computer readable storage medium includes a magnetic or optical disk storage device, solid state storage devices such as flash memory, or other non-volatile memory device or devices. The computer readable instructions stored on the non-transitory computer readable storage medium may be in source code, assembly language code, object code, or other instruction format that is interpreted and/or executable by one or more processors.

Claims

1. A non-transitory computer readable program storage unit encoded with instructions that, when executed by a computer, perform a method of treating an epileptic seizure in a patient, comprising: detecting said epileptic seizure, based on body data from said patient; andreducing a flow of blood to a brain of said patient in response to said detected seizure;wherein said reducing is effected by at least one of:applying a pressure, applying a cooling, or administering a vasoconstrictive agent to a vessel supplying blood to at least a portion of the brain.

2. The non-transitory computer readable program storage unit of claim 1, wherein: said pressure is applied to at least a portion of a posterior cerebral artery or a branch thereof,said cooling is applied to at least a portion of said posterior cerebral artery, said branch thereof, a carotid artery, or a branch thereof, orsaid vasoconstrictive agent is administered to at least a portion of said posterior cerebral artery, said branch thereof, said carotid artery, or said branch thereof.

3. The non-transitory computer readable program storage unit of claim 1, further comprising identifying an epileptogenic or pro-epileptogenic brain region, and wherein said vessel supplies blood to said brain region.

4. The non-transitory computer readable program storage unit of claim 1, wherein said reducing is effected by said applying said pressure.

5. The non-transitory computer readable program storage unit of claim 4, wherein said pressure is applied by a circumarterial cuff to restrict blood flow in said vessel.

6. The non-transitory computer readable program storage unit of claim 1, wherein said reducing is effected by said applying said cooling.

7. The non-transitory computer readable program storage unit of claim 6, wherein said cooling is applied by a thermoelectric device or a refrigerant system.

8. The non-transitory computer readable program storage unit of claim 1, wherein said reducing is effected by said administering said vasoconstrictive agent.

9. The non-transitory computer readable program storage unit of claim 1, further comprising stopping said therapy in response to at least one of a) a termination of said seizure; b) an increase in power in the 0-4 Hz frequency band of an EEG signal in at least one brain region; c) a decrease in power in all EEG frequency bands in at least one brain region; d) lapse of a therapy time period or e) undesirable side effect selected from: an impairment of a neurological function in at least one brain region or an impairment in tissue.

10. The non-transitory computer readable program storage unit of claim 9, wherein said stopping said therapy comprises at least gradually releasing said pressure, gradually rewarming, or gradually withdrawing the vasoconstrictor agent.

11. A non-transitory computer readable program storage unit encoded with instructions that, when executed by a computer, perform a method of treating an epileptic seizure in a patient, comprising: detecting said epileptic seizure, based on body data from said patient; anddecreasing the metabolic rate of epileptogenic or proepileptogenic tissue of the brain by cooling the blood flowing to a blood vessel selected from a carotid artery, a carotid artery branch, a vertebral artery, or a vertebral artery branch of said patient in response to said detected seizure.

12. The non-transitory computer readable program storage unit of claim 11, wherein said cooling is applied by a thermoelectric device or a refrigerant system.

13. The non-transitory computer readable program storage unit of claim 11, further comprising stopping said therapy in response to at least one of a) a termination of said seizure; b) an increase in power in the 0-4 Hz frequency band of an EEG signal in at least one brain region; c) a decrease in power in all EEG frequency bands in at least one brain region; d) lapse of a therapy time period or e) an undesirable side effect selected from: an impairment of a neurological function in at least one brain region or an impairment in tissue.

14. The non-transitory computer readable program storage unit of claim 13, wherein said stopping said therapy comprises gradually rewarming said blood.

15. The non-transitory computer readable program storage unit of claim 11, further comprising performing an action in response to detecting said epileptic seizure, wherein said action comprises at least one of: providing a second therapy;logging at least one of detecting said epileptic seizure, an environmental circumstance associated with the seizure, or an action taken in response to the seizure; orproviding a warning of detecting said epileptic seizure.

16. The non-transitory computer readable program storage unit of claim 15, wherein providing a second therapy comprises providing at least one of an electrical therapy or a chemical therapy.

17. A medical device system, comprising: an epileptic seizure detection module configured to detect an occurrence of an epileptic seizure, based on body data from a patient;a therapy device selected from: a pressure device configured to apply pressure to a vessel supplying blood to at least a portion of the brain of a patient,a cooling device configured to cool a vessel supplying blood to at least a portion of the brain of said patient, ora vasoconstrictive agent device configured to administer a vasoconstrictive agent to a vessel supplying blood to at least a portion of the brain of said patient.

18. The medical device system of claim 17, wherein said pressure device is configured to applied said pressure to at least a portion of a blood vessel selected from a carotid artery, a carotid artery branch, a vertebral artery, or a vertebral artery branch, said cooling device is configured to apply said cooling to at least a portion of said blood vessel selected from a carotid artery, a carotid artery branch, a vertebral artery, or a vertebral artery branch, orsaid vasoconstrictive agent device is configured to administer said vasoconstrictive agent to at least a portion of said blood vessel selected from a carotid artery, a carotid artery branch, a vertebral artery, or a vertebral artery branch.

19. The medical device system of claim 17, wherein said vessel supplies blood to an epileptogenic or proepileptogenic region of said brain.

20. The medical device system of claim 17, wherein said therapy device is configured to gradually release said pressure, gradually rewarm said vessel, or gradually withdraw the vasoconstrictor agent in response to said directive to stop said therapy.