Micro-invasive neural system for delivering therapeutic agents for the treatment of neurological disorders

Abstract

ABSTRACT Systems and methods for treating neurological disorders, such as epilepsy, where a drug delivery device is implanted adjacent to a micro-region within the brain for local administration of a drug thereto, where local administration of the drug into the micro-region is effective to treat the neurological disorder while substantially avoiding adverse side effects.

Description

MICRO-INVASIVE NEURAL SYSTEM FOR DELIVERING THERAPEUTIC AGENTS FOR THE TREATMENT OF NEUROLOGICAL DISORDERSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 560,526, filed March 1, 2024. which is incorporated herein by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with Government support under EB027717 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] Epilepsy is one of the most common neurological disorders, affecting nearly 50 million people worldwide. It is characterized by abnormal electrical discharges in the brain leading to recurrent spontaneous seizures that can be classified as either generalized (effecting the entire brain) or focal (affecting one discrete region of the brain). Focal seizures are more prevalent and account for roughly 60% of epilepsy cases. Oral administration of antiseizure medications (ASMs) is the gold standard for managing focal epilepsy, but high doses of ASMs, or multiple ASMs, are often needed to achieve seizure control. This can cause severe biological, cognitive, and behavioral effects that often lead to drug discontinuation for many patients.

[0004] While the most common ASMs, such as phenobarbital, carbamazepine, phenytoin, and valproic acid, may be easily partitioned into the brain, the therapeutic index for these drugs is very narrow. Phenobarbital, for example, is an allosteric modulator that interacts with neuronal GABAA receptors to increase the flow of chloride ions into the neuron and raise the action potential threshold. Direct activation of the GABA receptor is also thought to contribute to phenobarbital’s therapeutic effect at high concentrations. The decrease of neuron excitability is what is desired in epilepsy therapy, but GABAA receptors are ubiquitous in the central nervous system and not localized to the focal origin of the seizures. Thus, systemic dosing of phenobarbital exposes the entire central nervous system to the effects of the drug, often resulting in sedation. Finding optimal dosing for any given patient is a challenge as the balance of what is required for seizure control and what can be tolerated for a given patient is frequently not obtainable.

[0005] Moreover, approximately two-thirds of patients with focal epilepsy will not tolerate doses of ASMs sufficient to control seizures. Those patients are referred to as drug-resistant (refractory). The number of patients with drug-resistance has not improved in the past 20 years despite many new ASMs being introduced into the clinic, highlighting the need for newtreatment strategies. Drug-resistant focal epilepsy affects a significant population and there are limited treatment options. Oral administration of ASMs can provide seizure control for some patients but is ineffective except sometimes at very high doses for others. Surgical resection and laser interstitial thermal therapy are the current gold standard of care for patients unresponsive to ASMs. These procedures are, however, ablative and heavily underutilized due to their invasive nature, inaccessibility of seizure foci location, and variability in success.

[0006] As such, there is a need for minimally invasive, non-ablative modalities that can target seizure foci and avoid critical brain structures to preserve function.SUMMARY

[0007] In one aspect, a method of treating epilepsy in a patient is provided. In particular embodiments, the method includes implanting a micro-invasive neural infusion device at least partially within at least one selected micro-region within the patient’s brain; locally administering, via the implanted micro-invasive neural infusion device, an anti-seizure medication directly into the at least one selected micro-region within the patient’s brain; wherein the local administration of the anti-seizure medication directly into the at least one selected micro-region within the patient’s brain is effective to treat the epilepsy while substantially avoiding adverse side effects in the patient that would be observed with systemic administration of the medication at a therapeutically effective systemic dose.

[0008] In another aspect, a method of treating a neurological disorder in a patient is provided. In some embodiments, the method includes: identifying a micro-region within the patient's brain as a source of the neurological disorder; implanting a micro-invasive neural infusion device within the identified micro-region within the patient’s brain, wherein the micro- invasive neural infusion device is a microfluidic pump system; and locally administering less than 0.05 mg / kg of a therapeutic agent, via the micro-invasive neural infusion device directly to the identified micro-region within the patient's brain, wherein the local administration of less than 0.05 mg / kg of the therapeutic agent is effective to treat the neurological disorder while substantially avoiding adverse side effects in the patient that would be observed with systemic administration of the medication at a therapeutically effective systemic dose.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The detailed description is set forth with reference to the accompanying drawings. The use of the same reference numerals may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those illustrated in the drawings, and some elements and / or components may not be present in various embodiments. Elements and / or components are not necessarily drawn to scale.

[0010] FIG. 1 A is a perspective view of micro-invasive neural infusion device for local treatment of seizures, according to one or more embodiments of the present disclosure.

[0011] FIG. IB is a cross-sectional view of the micro-invasive neural infusion device of FIG. 1 A, according to one or more embodiments of the present disclosure.

[0012] FIG. 2 is a flow chart of a method for locally treating seizures using a micro-invasive neural infusion device, according to one or more embodiments of the present disclosure.

[0013] FIG. 3A is an image of an exemplary micro-invasive neural infusion device for local treatment of seizures, according to one or more embodiments of the present disclosure.

[0014] FIG. 3B is a graph of the infusion profiles of exemplary7micro-invasive neural infusion devices for local treatment of seizures, according to one or more embodiments of the present disclosure.

[0015] FIG. 3C is a micro-CT image after implantation of a micro-invasive neural infusion device for local treatment of seizures after one week, according to one or more embodiments of the present disclosure.

[0016] FIG. 4A is a schematic depicting the insertion location of a micro-invasive neural infusion device for local treatment of seizures and an electrode for measuring seizure activity, according to one or more embodiments of the present disclosure.

[0017] FIG. 4B is an image of a micro-invasive neural infusion device for local treatment of seizures and an electrode chronically implanted in a mouse, according to one or more embodiments of the present disclosure.

[0018] FIG. 4C is an image of a mouse brain slice depicting infusion of dye into the electrode region from the micro-invasive neural infusion device for local treatment of seizures, according to one or more embodiments of the present disclosure.

[0019] FIGS. 5A-5D are graphs of the number of seizure-like events in individual mice 24- 72 hours after treatment, according to one or more embodiments of the present disclosure.

[0020] FIG. 6A depicts representative EEG recordings from kainite model epileptic mice, according to one or more embodiments of the present disclosure.

[0021] FIG. 6B depicts variations in the number and duration of seizure-like events over a period of 12 hours, according to one or more embodiments of the present disclosure.

[0022] FIG. 7 A depicts the number of seizure-like events recorded in a group of mice before and after local and systemic treatment with phenobarbital, according to one or more embodiments of the present disclosure.

[0023] FIG. 7B depicts the number of seizure-like events recorded in a group of mice before and after local and systemic treatment with valproate, according to one or more embodiments of the present disclosure.

[0024] FIG. 7C depicts the number of seizure-like events recorded in a group of mice before and after local and systemic administration of a vehicle, according to one or more embodiments of the present disclosure.

[0025] FIG. 7D depicts the percent change in the number of seizure-like events before and after local and systemic administration of the vehicle, as compared to the phenobarbital and valproate treatments, according to one or more embodiments of the present disclosure.

[0026] FIGS. 8A-8E are graphs depicting the frequency of seizure-like events before and after local administration of phenobarbital or valproate at various doses, according to one or more embodiments of the present disclosure.

[0027] FIGS. 8F-8J are graphs depicting the frequency of seizure-like events before and after systemic administration of phenobarbital or valproate at various doses, according to one or more embodiments of the present disclosure.

[0028] FIG. 9A is a graph comparing the cumulative number of seizure-like events over time following systemic administration of drug or vehicle.

[0029] FIG. 9B is a graph comparing the cumulative number of seizure-like events over time following local administration of drug or vehicle.

[0030] FIGS. 10A-10B are graphs depicting the effects of systemic and local administration of phenobarbital and valproate on rotarod performance, according to one or more embodiments of the present disclosure.

[0031] FIGS. 10C-10D are graphs depicting the effects of systemic and local administration of phenobarbital and valproate on open-field performance, according to one or more embodiments of the present disclosure.

[0032] FIG. 11 A is a graph depicting the frequency of seizure-like events recorded before and after local administration of phenobarbital.

[0033] FIG. 1 IB is a graph depicting the average rate of seizure-like events recorded before and after local administration of phenobarbital.

[0034] FIG. 11C is a graph depicting the frequency of seizure-like events recorded before and after local administration of a vehicle.

[0035] FIG. 1 ID is a graph depicting the average rate of seizure-like events recorded before and after local administration of a vehicle.

[0036] FIG. 12A is a graph depicting the frequency of seizure-like events recorded before and after systemic administration of phenobarbital.

[0037] FIG. 12B is a graph depicting the average rate of seizure-like events recorded before and after systemic administration of phenobarbital.

[0038] FIG. 12C is a graph depicting the frequency of seizure-like events recorded before and after systemic administration of a vehicle.

[0039] FIG. 12D is a graph depicting the average rate of seizure-like events recorded before and after systemic administration of a vehicle.DETAILED DESCRIPTION

[0040] Systems and methods for locally administering commonly prescribed therapeutic agents for treating neurological disorders, particularly epilepsy, have been developed to effectively treat epileptic seizures. In a particularly advantageous embodiment, a micro-invasive neural infusion device is implanted into the brain of a patient to locally administer an antiseizure medication directly to the patient’s brain. In preferred embodiments, the micro-invasive neural infusion device is implanted at or near the epileptogenic region of the patient’s brain.

[0041] The micro-invasive neural infusion devices described herein may therefore be used to treat epilepsy while substantially avoiding adverse side effects in the patient that would be observed with systemic administration of the same medication. While local administration requires that a significantly smaller dose of anti-seizure medication be administered, as compared to systemic administration, there is no reduction of efficacy with the treatments disclosed herein.

[0042] In some embodiments, the therapeutically effective dose of a locally administered anti-seizure medication is more than 1000 less than the requisite systemically administered dose. For example, the therapeutically effective amount of an anti-seizure medication, when delivered according to the systems and methods described herein, is less than 0.05 mg / kg, such as less than 0.04 mg / kg. less than 0.03 mg / kg, less than 0.02 mg / kg, or less than 0.01 mg / kg. According to a preferred embodiment, the therapeutically effective dose is from about 0.004 mg / kg to 0.017 mg / kg.

[0043] In embodiments, delivery' of the drug to the patient’s brain may be continuous, or in bursts at a predefined interval of time, such as every day, every 12 hours, every hour, every 30 minutes, or every minute.

[0044] In some embodiments, the therapeutic agent is an anti-seizure medication, such as phenobarbital, valproate, or a combination thereof. In other embodiments, other therapeutic agents known in the art or developed may be used.

[0045] In some embodiments, the patient’s epilepsy is focal epilepsy, and the epileptogenic region of the patient’s brain is the sub-region from which the focal seizures are originating. The focal region may be in the patient’s temporal lobe, frontal lobe, hippocampus, or cerebellum.

[0046] The micro-region, or sub-region, of the brain in which the drug is administered may be an identified epileptic focus. Epileptogenic lesions are often identified using magnetic resonance imaging (MRI), computed tomography (CT), or positron emission tomography (PET) with MRI being the dominant imaging method due to its high sensitivity and specificity (Bianchin, M.M. et al. Cognitive and surgical outcome in mesial temporal lobe epilepsy associated with hippocampal sclerosis plus neurocysticercosis: a cohort study. PLoS One 8, e60949 (2013); Newton, R.W. The epilepsies: Seizures, syndromes and management. J. R. Soc. Med. 99:42-43 (2006)). High-resolution MRI. particularly with specialized protocols such as T1 -weighted, T2-weighted, fluid-attenuated inversion recovery, and diffusion-weighted imaging, helps visualize structural abnormalities such as hippocampal sclerosis (Bemasconi, A., Bemasconi, N., Bernhardt, B.C. & Schrader, D. Advances in MRI for ‘cryptogenic ’ epilepsies. Nat. Rev. Neurol. 7:99-108 (2011)). Electroencephalography (EEG) is also used to localize seizure onset zones by detecting abnormal electrical activity. Depth electrodes placed in the deep brain are often required for precise localization. These electrodes are placed under image guidance with minimal complications (Koubeissi, M. Z. Difficult-to-localize intractable focal epilepsy: An ‘in-depth ' look. Epilepsy Curr. 13:88-89 (2013); Carlson, A.A., Rutishauser, U. & Mamelak, A.N. Safety and utility of hybrid depth electrodes for seizure localization and singleunit neuronal recording. Stereotact. Funct. Neurosurg. 96:31 1-19 (201 )).

[0047] The micro-invasive neural infusion devices described herein may therefore be used to provide long term treatment, following implantation, to selectively modulate neuronal activity using sub-microliter infusions of drugs into deep brain structures. This microinvasive implant may also be applied to a variety of diseases, including but not limited to epilepsy, thereby enabling a deeper understanding of focal drug delivery in the treatment of neurological disorders.

[0048] The systems and methods disclosed herein can be adapted for use with essentially any medical device configure for placement in contact with brain tissues or other neurological tissues over an extended period. In one embodiment, the medical device is a neural implant as known in the art, which may be configured to deliver one or more drugs (e.g., one or more antiseizure medications) to a region of interest within a patient's brain. Essentially any type of neural implant may be used herein. The neural implant may include a narrow elongated body portion, which may be substantially rigid and may include one or more channels for carryingfluids for injection. The neural implant may comprise a cannula. In some instances, the neural implant includes a chronic intracranial implant configured to facilitate the administration of a therapeutic agent to specific anatomical (e.g., brain) nuclei. In some instances, the neural implant may be a passive device, an active device, or a combination thereof.

[0049] The neural implant generally is configured to be partially or fully implantable in a patient. The patient may be human or other mammal. In order to effectively treat neurological disorders, such as epilepsy, the devices such as the neural implants often require chronic operation. A suitable neural implant as described herein should operate effectively at the time of implantation and continue to do so in the presence of bodily biological responses to the device.

[0050] In some embodiments, the neural implant also includes a microfluidic pump system to facilitate delivery of the therapeutic agent. In some embodiments, the microfluidic pump system is a peristaltic pump system. In one embodiment, the peristaltic pumps include an elongated tubular member having a first end, an opposed second end, and a wall (e.g., an elastic wall) defining a flow channel extending between the first and second ends; and a series of actuator wires, each comprising a shape memory alloy, wherein the actuator wires extend across and at least partially around the outer surface of the elastic wall at spaced positions along the length of the tubular member. That is, the actuator wires are in contact with the wall at positions spaced from one another. The actuator wires are configured to reversibly and directly compress the elastic wall, and thereby constrict regions of the flow channel, upon an electrothermally induced phase transition of the shape memory alloy. The reversibility may be complete or partial so long as the pumping functionality is provided.

[0051] The elongated tubular member may be constructed of any suitable material(s) that can be compressed and that are compatible with the fluid to be transported and the environment of use. In some embodiments, the elongated tubular member comprises an elastomeric material. In some embodiments, the elongated tubular member comprises a biocompatible elastomeric material. For example, in some embodiments, the elongated tubular member comprises silicone or polyurethane.

[0052] In various embodiments, the tubular member is formed by a molding, casting, extrusion, or additive manufacturing process, adapted or known in the art. The flow channel maybe formed simultaneously with the body of the tubular member. Alternatively, a subsequent process can be used in which a portion of the structural material is removed from the body in a region to define / form the flow channel.

[0053] In some embodiments, the actuator wires, or at least a portion of a series of actuator wires, are configured to function as one or more check valves, to prevent back flow. Forexample, an actuator wire in an activated, or contracted, state may completely constrict the flow channel such that essentially no fluid can flow through the channel at that cross-sectional point in the channel.

[0054] In some embodiments, the pump is part of pumping system configured for fluid delivery'. In embodiments, the nanofluidic peristaltic pump described herein is coupled to a fluid source.

[0055] For example, the peristaltic pump may be configured to transport a fluid comprising a drug, from a fluid source comprises the fluid to a delivery site distal from the fluid source. In such an embodiment, the flow channel at one end of the tubular member of the pump is in fluid communication with the fluid source and the opposed second end of the tubular member is in fluid communication with the delivery site. The sequential activation and deactivation of the actuator wires causes the drug-containing fluid to flow from the fluid source, through the flow channel from the first end toward the second end, and to the delivery site.

[0056] In some embodiments, where the peristaltic pump is part of a neural implant, one or more microtubes are included between the second end (the discharge end) of the tubular member of the pump and the delivery site. That is. the microtubes are operably in fluid communication with the pump. Such microtubes serve as fluid conduits, or infusion channels. The microtube may be formed of any suitable material, such as a biocompatible material that is also compatible with the drug fluid. In some preferred embodiments, the microtube is formed of a borosilicate glass.

[0057] In some embodiments, the fluid includes the drug and a liquid excipient vehicle for the drug. For example, in some embodiments, the fluid includes a drug and water or a saline solution. Other suitable excipients are known in the art and may be included as appropriate. The drug may be essentially any prophylactic or therapeutic agents, or any active pharmaceutical ingredient, known in the art. The fluid drug may include a neuromodulating agent. In some embodiments, the neuromodulating agent is an anti-seizure medication, such as phenobarbital or valproate. Other neuromodulating agents know n in the art also may be used.

[0058] Additional embodiments of neural implants and pump systems as described herein are provided in greater detail in U.S. Patent Application Publication No. 2016 / 0354034 to Spencer et al., and U.S. Patent Application Publication No. 2019 / 0344057 to Cima et al., which are hereby incorporated by reference herein.

[0059] FIGS. 1 A-1B depict an embodiment of a micro-invasive neural infusion device for use in the treatment of neurological disorders, such as epilepsy. The neural infusion device 100 includes a device body 110 and a capillary’ 120 for transporting and delivering a therapeuticagent from the device to the patient’s brain. An flow channel 125 may fluidically connect the capillary 120 with a fluid source 130 containing a liquid form of a therapeutic agent therein. In some embodiments, as shown in FIGS. 1A-1B, the device 100 also includes a pump 140 for controlling the rate of diffusion of the drug from the device. The pump 140 may be, for example, a microfluidic peristaltic pump. However, those of ordinary skill in the art would recognize that any microfluidic pump system known in the art could be suitable for use with the micro-invasive neural infusion devices disclosed herein.

[0060] Referring now to FIG. 2, a method 200 of treating epilepsy using the micro-invasive neural infusion devices described herein is also provided. First, the location of the origin of the patient's focal seizures is to be identified (210). After the sub-region of the brain from which the focal seizures are originating is identified, a micro-invasive neural infusion device is implanted within this sub-region of the patient’s brain (220). In a preferred embodiment, the micro- invasive neural infusion device is implanted so that the capillary is as close to the origin local of the patient's focal seizures as possible. After the device is implanted within the correct region of the patient’s brain, an anti-seizure medication may be delivered to the patient from the device (230).

[0061] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the,” include plural referents unless the context clearly dictates otherw ise. The term “about,” as used herein, indicates the value of a given quantity can include quantities ranging within 10% of the stated value, or optionally, within 5% of the stated value, or in some embodiments, within 1 % of the stated value.

[0062] While the disclosure has been described with reference to a number of exemplary' embodiments, it would be understood by those skilled in the art that the disclosure is not limited to such disclosed embodiments. Rather, the disclosed embodiments can be modified to incorporate any number of variations, alterations, substitutions, or equivalent arrangements not described therein, but which are commensurate with the spirit and scope of the disclosure.

[0063] The invention can be further understood with reference to the follow ing non-limiting examples.Example 1. Development of Micro-Invasive Neural Infusion (MINI) Platform

[0064] It was hypothesized that physically delivering drug to a seizure focus in sufficient quantities to arrest seizure-like activity w ould limit adverse events and increase the therapeutic window'. An implantable neural drug delivery system (micro-invasive neural implant infusion platform (MINI)) was developed to deliver microliter infusion volumes to deep brain structures with high spatial resolution. These systems demonstrated the ability' to delivery' drugs preciselyand repeatedly to discrete brain micro-regions of awake and behaving rodents for up to a year post-implantation. MINI technology was also assessed to directly infuse ASMs near a seizure focus in an intrahippocampal kainate (IHK) mouse model of mesial temporal lobe epilepsy (TLE).

[0065] The IHK model of TLE is a validated animal model that uses intra-hippocampal injections of kainate to produce chronic spontaneous nonconvulsive (electrographic) seizures originating from the area of kainate injection. These electrographic seizures, commonly referred to as seizure-like events (SLEs) are comprised of high-voltage spike waves that occur at frequencies between 10-60 per hour, making it ideal for acute drug testing. Two common ASMs, phenobarbital (PB) and valproate (VP A), were given both locally and systemically to IHK mice to determine the effect on seizure activity. Rotarod and open field tests were also performed in these mice to examine whether adverse effects could be reduced with local delivery of ASMs compared to systemic administration. This study demonstrates the ability7of this neural drug deliver platform to suppress focal seizure activity and minimize adverse effects by delivering micro doses of ASMs to the seizure focus.MINI Implant Fabrication

[0066] MINI devices were fabricated using a borosilicate capillary (inner diameter = 50 pm, outer diameter = 80 pm, VitroCom Inc.) inserted into polyether ether ketone tubing (inner diameter = 0.25 mm, outer diameter = 1.59 mm, Idex Health & Science) (FIG. 3A). PEEK tubing was cut to 10 mm in length and manufactured with an interior bore of 250 pm and an exterior bore of 1 .59 mm. Borosilicate glass capillaries are polished via fiber optic polisher and inserted in PEEK tubing with 5mm overlap and epoxied in place. Borosilicate capillaries were interfaced with poly ether-ether-ketone (PEEK) tubing to provide fluidic connection for commercial microfluidic pump systems. Capillaries were cut to 1.5 cm in length and then inserted in the PEEK until 1 cm was left exposed. The capillary was then cut to a length of 2.9 mm. UV curable epoxy (Loctite 4305, Henkel Corp.) was used to secure the two components together and the PEEK tubing was cut to 1.5 cm in length.

[0067] In vitro characterization was done to confirm the fluid-delivery characteristics of the devices (FIGS. 3B-3C). To confirm fluid delivers7, 1 pl of deionized water was infused at a rate of 300 nl / min through cannula devices and measured using a micro balance. Devices delivered an average of 1.003 ± 0.058 pl (n = 5) (FIG. 3B). Devices were also implanted into the nucleus accumbens of rats. Animals were anesthetized and infused with 1 pl of lohexol contrast. Infusions occupied a volume of 2.93 ± 0.29 mm3 (n=7) (FIG. 3C, white arrow indicates region of bolus infusion).Intrahippocampal Kainate Model and MINI Implantation

[0068] Male C57bl / 6 mice (n = 25) weighing between 22-26 g were surgically prepared. All surgical procedures were performed under general an-aesthesia (1.5% isoflurane in O2) and stereotaxic guidance. A Dremel drill was used to create three shallow screw holes where stainless steel anchor screws were affixed above the ipsilateral and contralateral frontal cortex and the contralateral somatosensory cortex. An additional hole was drilled over the right hemisphere and kainic acid (100 nl of a 20 mM solution) was injected into CAI of the right dorsal hippocampus (AP: -1.8, ML: 1.3, DV: -2.0). MINI devices were implanted adjacent to the site of kainate injection (AP: -2.0, ML: 1.3, DV:- 2.0) (FIG. 4A). Device placement was verified in pilot studies and following study conclusion via post-mortem infusions of trypan blue dye through the device (FIG. 4C). For the EEG depth electrode, holes were drilled over the right hemisphere ventral hippocampus and cerebellum; a bipolar platinum iridium depth electrode (MS333 / 6-B / SPC, Plastics One Inc.) was then implanted into area CAI (AP: -2.7, ML: 1.8, DV: -1.8) and a reference electrode over the cerebellum. The depth electrode was implanted 0.7 mm posterior to the MINI device to allow for adequate space to connect the EEG tether for recording. The EEG electrode and MINI device were fixed in place and a headcap was created with dental acrylic cement (FIG. 4B). Antibiotic ointment was applied around the incision site and a single dose of enrofloxacin (20 mg / kg subcutaneously) was administered.

[0069] Video-EEG (vEEG) monitoring began directly following kainic acid injection to verify status epilepticus (SE) and was discontinued the following morning to allow the animals to recover. To verify that mice had developed spontaneous electrographic and / or generalized behavioral seizures, 24 / 7 vEEG resumed starting 6 weeks after SE. Mice were connected via a tether to a rotating commutator (8BSL3CX, Plastics One Inc.), which in-tum was connected to an EEG100C amplifier (500 Hz sampling rate, low pass filter: 100 Hz, high pass filter: 0. 1 Hz) and digitized by an MP160 Recording system (BioPac Systems Inc.). Simultaneous video was captured by a DVP 7020BE Capture card (Advantech). vEEG data were synchronized and written to disk using custom software. Mice were housed singly in clear acrylic cages (one per cage).Prues

[0070] PB and VPA and their respective vehicles were evaluated in IHK mice. These ASMs were chosen because they are well characterized and potent. They also have different mechanisms of action and are both shown to be effective at reducing SLEs in this animal model following systemic administration. Both drugs were tested locally and systemically at two different doses. The systemic doses chosen were found to be effective in previous studies in thesame animal model. Local dose selection was based on ASM concentrations observed in the brain after equivalent systemic administration. All systemic administrations were given intraperitoneally in a volume of 10 ml / kg. PB, 20 and 60 mg / kg, was dissolved in saline (0.9% NaCl) and VP A, 300 and 400 mg / kg, was dissolved in 0.5% methylcellulose (Sigma) to make a fine suspension. Local administration through the MINI consisted of drug solution at two different concentrations. PB was dissolved in 1 x PBS to a concentration of 110 or 400 pg / ml, and VPA was dissolved in 1 x PBS to a concentration of 700 or 1160 pg / ml. All local infusions were given in a delivery volume of 1 pl at a rate of 0.3 pl / min. Local delivery volume was chosen following in vivo imaging studies using infusions of contrast agent to determine bolus delivery' size and coverage (FIGS. 3A-3C). This delivery volume was further verified in preliminary’ experiments. Local doses are converted to mg / kg to compare to systemic doses by dividing the amount of drug delivered by the average mouse weight (24 g) to give local PB doses of 0.005 mg / kg (0.11 pg) and 0.017 mg / kg (0.4 pg), and VPA doses of 0.029 mg / kg (0.7 pg) and 0.048 mg / kg (1.16 pg). Saline (0.9% NaCl) was used as the vehicle control for systemic experiments and 1XPBS was used as the vehicle control for local administration.Drug Effects on Seizure-Like Events

[0071] The effect of ASMs on SLEs was assessed 8 weeks after SE. A group of 13 mice with frequent SLEs was used for the experiments. The final group size analyzed per treatment was between six and nine mice. All mice were used for several treatments; the minimum time interval between two drug experiments in the same animal was at least 48 h. A return to baseline SLE activity was confirmed for each experimental condition (FIGS. 5A-5D). Data was collected for drug treatment conditions where seizure-like events (SLEs) did not return to baseline activity' within the 2 hours of EEG recording following treatment, with baseline being defined as the number of SLEs during the 45 m immediately prior to treatment. The comparison of SLE activity during treatment time and 24-72 hours later was not significantly different for all drug treatment conditions shown. Group sizes differed for the various treatments because not all mice were used for all treatments, and sometimes the quality of the EEG in individual mice was not sufficient to allow adequate analysis of drug effects; accordingly, these mice were excluded from the final analysis. The sequence of treatments was randomized so that different doses of the same drug were not tested consecutively but in random order at different intervals after the initial insult in groups of mice.

[0072] Baseline EEG activity' was recorded for 1 h prior to treatment and 1 h immediately following treatment, so that each animal was used as its own control. SLE incidence was evaluated and reported for the 45 min immediately before treatment and for the last 45 min ofrecording following treatment (15-60 min after injection). The first 15 min following injection were not evaluated to avoid any impact of rodent handling and injections on SLEs over this time period. EEG data were analyzed off-line using automated algorithms for SLE detection and quantification (Zeidler et al. ,36 RRID:SCR_016344). Manual validation of all SLEs was then performed. SLEs were de-fined as regular spike clusters with a duration >3 s, a spike wave frequency >2 Hz and an amplitude of at least twice the baseline EEG.Statistical Analysis

[0073] SLEs observed in the EEG during the 45-min recording period before drug treatment were normalized to 100% and compared with the SLEs counted in the EEG in the 45-min recording period after treatment. Paired t-tests were performed to compare differences between baseline SLE activity and treatment. Differences between groups were compared using a repeated-measures ANOVA followed by Bonferroni’s test for post hoc comparisons. Unpaired t- tests were used in case of comparisons between only two groups. P < 0.05 was considered significant.Development of SLEs in the Mouse Intrahippocampal Kainate Model of Epilepsy

[0074] EEG recordings from epileptic mice from the kainite model were taken. Spontaneous recurrent SLEs (FIG. 6 A(i)) lasting an average of 9.5 s with an average spike frequency of 2.7 Hz were recorded from the electrode in the injected hippocampus 6 weeks after kainate injection. Most of these SLEs were characterized by bursts of HVSWs which were mostly not associated with any obvious behavioral alterations. HVSWs can show either no clear evolution or some evolution in frequency or pattern. Unilateral hippocampal paroxysmal discharges (HPDs) with high frequency (>5 Hz) of low-voltage polymorphic spikes were only rarely observed.

[0075] The number of SLEs in a group of six IHK mice were analyzed over 12 consecutive hours to determine the variation in SLE incidence over time. The average number of SLEs per hour (40 ± 2 / h) was consistent over this period as shown in FIG. 6B(i), without significant interhour variation (P = 0. 110; one-way ANOVA). This is consistent with the expectation of this animal model. In addition to the focal SLEs, two mice also displayed generalized tonic-clonic seizures associated with typical paroxysmal EEG activity (FIG. 6A(ii)) during this recording period. The effect of such convulsive seizures led to a decrease in subsequent SLEs which explains some of the variation show n in FIG. 6B(i). The variation in SLE duration in these mice was also evaluated over the same 12-h period (FIG. 6B(ii)) and it w as found that the duration was consistent over time (P = 0.312; one-way ANOVA).Effect of Local vs. Systemic Delivery of ASMs on Spontaneous Focal Seizure Incidence and Duration

[0076] The number of SLEs recorded from the whole group of epileptic mice were calculated 45 min before drug treatment and 15 min-1 h after (i) intracerebral administration of 0.005 mg / kg (0.11 pg) or 0.017 mg / kg (0.4 pg) PB or (ii) intraperitoneal administration of 20 mg / kg or 60 mg / kg PB (FIG. 7A). The same data are shown following (i) intracerebral administration of 0.029 mg / kg (0.7 pg) or 0.048 mg / kg (1.16 pg) VPA or (ii) intraperitoneal administration of 300 mg / kg or 400 mg / kg VPA (FIG. 7B), and for (i) intracerebral or (ii) intraperitoneal administration of vehicle (FIG. 7C). To allow comparisons between different treatments, SLEs counted in the EEG in the 45-min block before drug treatment were normalized to 100% and compared with the SLEs counted in the EEG in the 45-min block after treatment. The percent change in SLE incidence 45 min before drug treatment and 15 min-1 h after both intraperitoneal and intracerebral delivery of (i) PB or (ii) VPA was also determined (FIG. 7D)

[0077] Local delivery of PB through the MINI device had a significant effect on the number of SLEs at 1-h post treatment compared to baseline. Just 0.005 mg / kg (0.11 pg) of PB delivered intracerebrally adjacent to the kainate focus in CAI significantly reduced the number of SLEs from baseline as seen in FIG. 7A(i), whereas the systemic equivalent dose of 20 mg / kg PB did not have a significant effect on SLE incidence (FIG. 7A(ii)). Both local and systemic delivery methods showed a dramatic reduction in the number of SLEs compared to baseline at higher doses of PB, with 4 / 9 mice having <1 SLE following local delivery of 0.017 mg / kg (0.4 pg) PB and 3 / 6 mice having <1 SLE following systemic delivery of 60 mg / kg PB. This shows that both local and systemic delivery of PB have a dose-dependent effect on SLEs, but much higher doses of PB are required systemically to have a significant effect compared to local delivery. FIG. 7B(i) shows that local delivery of VPA through the MINI device also reduced the number of SLEs. This effect was dose-dependent with the largest local infusion of 0.048 mg / kg (1.16 pg) VPA eliminating SLEs in 5 / 7 mice. Unlike PB, however, both systemic doses of VPA given had a significant effect on SLE incidence (FIG. 7B(ii)) with the highest VPA dose of 400 mg / kg eliminating SLEs in 4 / 6 mice. Both local and systemic delivery of vehicle had no effect on the number of SLEs (FIG. 7C) when measured 1 h after administration, although a slight reduction in SLE incidence was seen in one mouse receiving systemic vehicle (15% reduction in SLEs from baseline) and in another mouse receiving local vehicle (30% reduction in SLEs from baseline). These per cent reduction values were used as a threshold to define individual responders to ASM therapy.

[0078] Responders and non-responders as well as the number of SLEs for each individual mouse can be seen in FIGS. 8A-8J. FIGS. 8A-8E show the frequency of seizure-like events (SLEs) in the EEG recorded from individual mice 45 m before drug treatment and 15 m -1 h after local administration of phenobarbital (PB) or valproate (VPA) at various doses. To allow comparisons between different treatments, seizure-like events counted in the EEG in the 45-m block before drug treatment were normalized to 100% and compared with the seizure-like events counted in the EEG in the 45-m block after treatment. FIGS. 8F-8J show the same data following systemic administration of PB or VPA at various doses. The largest reduction in SLE incidence seen in each vehicle group (local and systemic) was used as a threshold to define individual mouse response to drug therapy. For FIGS. 8A-8E, this was defined as at least a 30% decrease in SLE incidence compared to pre-drug control, and for FIGS. 8F-8J, this was defined as at least a 15% reduction in SLE incidence.

[0079] The percent change in SLE incidence compared to baseline for both local and systemic deliver^' of PB is illustrated in FIG. 7D(i). Both doses of PB delivered locally had a significant effect on SLE incidence compared to vehicle but only the highest dose of PB given systemically showed a significant reduction in SLEs compared to vehicle when measured at 1-h post treatment. FIG. 7D(ii) shows that all doses of VPA, regardless of delivery method, were effective in reducing SLE incidence compared to vehicle, but the extent of suppression was still dose dependent. FIG. 7D also shows that local delivery of ASMs is comparable, if not better than systemic delivery, at reducing SLEs in the IHK model of epilepsy. Drug effects on duration of SLEs were also analyzed in addition to analyzing their effect on SLE incidence (Table 1). Significance was not observed, however, as animals exhibiting zero SLEs following treatment could not be counted.Table 1. Effect of Phenobarbital and Valproate on Duration of Seizure-Like Events (SLEs).Drugs were given either locally or systemically via intraperitoneal injection. Values are given as mean ± SEM. n: number of mice. Statistical analysis was not performed on SLE duration before and after treatment, so no p-values are given. *Only animals that had SLEs after treatment were included in the SLE duration value.Time to Return to SLE Baseline Following, Local and Systemic Delivery of ASMs

[0080] The effect of ASMs on SLE incidence over time when delivered locally through a MINI device was evaluated as compared to systemic administration. EEG recordings were continued for a minimum of 1 h 45 m following all treatment conditions, up to 2 h 45 m. The cumulative number of SLEs per mouse group over time following each treatment condition is shown in FIGS. 9A-9B. The recording time beyond 1 h 45 m post treatment varied for each group.

[0081] The cumulative number of SLEs returned to the 45-min baseline count around 85 and 120 min post treatment following intraperitoneal injection of 300 mg / kg and 400 mg / kg VPA, respectively (FIG. 9A). This observation agrees with the short half-life of VPA (~60 min). The time for the SLE rate to return to baseline varied greatly for the dose of PB given systemically (FIG. 9A). Administration of 20 mg / kg PB caused little difference in the time it took to return to baseline compared to systemic vehicle delivery (60 min versus 65 min. respectively), whereas 60 mg / kg PB never reached its baseline SLE count during the 120 min post treatment recording period. This prolonged reduction in the SLE rate following 60 mg / kg PB can be explained by PB’s long half-life (~7 h). The pharmacodynamics of local delivery of PB and VPA differed andcan be seen in FIG. 9B. Local delivery' of the lowest dose of 0.029 mg / kg (0.7 pg) VPA was similar to its systemic counterpart and returned to the 45-min baseline SLE count around 90 min post treatment. The highest dose of VPA, however, never reached its baseline SLE count in the 140 min post-treatment recording period. The lowest local dose of PB took 1 10 min to reach its baseline SLE count, which is longer than its systemic counterpart, and the highest local dose of 0.017 mg / kg (0.4 pg) PB did reach its baseline SLE count, but only after 165 min of recording post treatment. Only the lowest local dose of VPA given was similar to systemic delivery in its SLE return rate. This suggests that ASMs are either cleared or metabolized differently when delivered directly to the brain parenchyma. EEG data ranging from 24 to 72 h post treatment were analyzed to confirm that the SLE rate did indeed return to base-line levels following each treatment condition (FIGS. 5A-5D).Effect of Local vs. Systemic Delivery of ASMs on Motor Function

[0082] The most significant drawback to current ASM therapy is the associated side effects, such as cognitive-motor impairment and organ toxicity7. It was investigated whether limiting the drug to one specific sub-region of the brain through local delivery7yvould mitigate these adverse events. Mice were tested for coordination and locomotive behaviors using the rotarod test and open field test.

[0083] Testing in these assays was performed in mice using the highest drug concentration or dose used in both infusion studies and systemic administration. Behavioral testing was performed following drug assessment on SLEs. Animals were allowed 30 min to acclimate to the testing room on any day experiments yvere conducted. All tests were conducted during the light cycle. Systemic injections of VPA and PB were administered by intraperitoneal injection 0.25 h or 0.5 h prior to testing, respectively. Local infusions of both VPA and PB were administered 0.25 h prior to testing. Motor impairment in mice was quantified using a rotarod assay wherein mice were placed on a rotating knurled steel rod (6 rpm) and the number of times they fell off the rotarod during a l-min observation period yvas recorded. Locomotive behaviors were assessed immediately following the rotarod assay using the open field test. Mice yvere singly placed in an automated open-field chamber (40 cm length x 40 cm width x 30 cm height) under ambient room light for 15 min. Fusion software (OmniTech Electronics. Columbus, OH, USA) yvas used to quantify horizontal and vertical movement as well as stereotypy. Only PB, given both systemically and locally, and a vehicle control yvere tested in the open field test.

[0084] FIG. 10A shows that intraperitoneal administration of 60 mg / kg PB resulted in significant motor impairment in the rotarod assay, with 6 / 8 mice falling at least one time duringthe 1 -min observation period. Systemic administration of 400 mg / kg VPA had a lesser, but still significant effect on coordination, with 3 / 8 mice falling at least once during the testing period (FIG. 10B). Local delivery of PB and VPA and systemic deliver}' of vehicle resulted in no recorded falls from the rotarod during the testing period (FIGS. 10A-10B).

[0085] The total distance travelled during a 15 min open field test for PB was significantly increased in mice receiving systemic PB compared to mice receiving either local PB or vehicle (FIG. 10C). The pattern of movement in FIG. 10D revealed that animals receiving systemic PB showed a significantly higher number of revolutions around the chamber compared to animals receiving vehicle or local PB. Both the total distance travelled and the number of total revolutions around the chamber did not vary significantly between local delivery of PB and vehicle.Analysis of Results

[0086] Focal delivery of two well-known ASMs (PB and VPA) to the kainate focus in CAI of the hippocampus using chronically implanted MINI devices significantly reduced focal seizure activity in the IHK mouse model of TLE. The attenuation of SLEs through local delivery of these compounds was significant at all doses of VPA and PB given. Local delivery was also as effective at reducing SLEs as systemic delivery but at one ten-thousandth the dose of systemic. This suggests that focal drug delivery7offers the potential for minimal side effects in addition to improved seizure control as the amount of drug delivered (0.004-0.017 mg / kg) is orders of magnitude lower than systemic administration (20-60 mg / kg). The effect of both local and systemic ASM delivery on motor coordination was measured using the rotarod and open- field test. Both tests have been historically used as qualitative behavioral tests to assess the potential for adverse effects of candidate drugs in mice. Animals receiving local infusions of PB and VPA showed no signs of toxicity or motor impairment at doses that significantly reduced SLE incidence. Systemic delivery of PB and VPA, by comparison, resulted in significant motor impairment in both tests. The rotarod assay showed that motor coordination was significantly impaired, indicated by an increase in the number of falls, with systemic administration of PB and VPA but not with local delivery of either.

[0087] The OFT also showed a difference in adverse effects but the results were a bit more surprising. It was found that systemic delivery7of 60 mg / kg PB induced a stimulatory7effect by' increasing overall motor activity7. Some groups have demonstrated that administration of high doses of PB to mice promotes hyperkinesia despite PB being classified as a sedative-hypnotic medication. Examining the pattern of locomotor activity7revealed that animals receiving systemic PB were traveling in circular motions around the chamber. This effect has not beennoted in previous literature and could indicate some form of cognitive impairment and disorientation as a side effect caused by the PB. It could also be an effect of the one-sided kainate lesion characteristic of the IHK model. In either case, animals receiving local administration of PB showed no difference in both the total distance traveled and the number of revolutions compared to systemic administration of saline vehicle. The results of both assays imply that local delivery of ASMs restricts the effect of the drug to the infusion zone, allowing for effective seizure management with little to no adverse effects.

[0088] This demonstrates that focal seizures can be suppressed, and adverse effects can be minimized, with local delivery' of ASMs to the seizure focus in in the IHK mouse model of TLE. Although the present study was restricted to the major ASMs PB and VP A, it is likely that the observations reported here can be extended to other ASMs and even non-pharmacological therapeutic agents such as neuropeptides or viral vectors. The the ability of the MINI device to maintain long-term viability following implantation and to selectively modulate neuronal activity using sub-microliter infusions of drugs into deep brain structures was also demonstrated. It is therefore expected that this microinvasive implant can be applied to a variety’ of disease states, enabling a deeper understanding of focal drug delivery in the treatment of neurological disorders.Example 2. Characterization of MINI Device Treatment Efficacy

[0089] Understanding the time course of effect for intracerebral delivery of ASMs is critical for clinical translation and for devising a dosing regimen for chronic drug studies. The time course of effect is relevant to how quickly any treatment effects will occur, and how long they will last. Example 1 demonstrates a suppressive effect on SLEs with local delivery’ that extended beyond the 60 min treatment mark used to measure drug effect on SLE incidence. Direct comparison between treatment groups was limited, however, as EEG recording time varied for each condition and baseline SLE activity was never reached for many treatment groups. To more accurately answer these research questions, further analysis in a cohort of IHK mice in which the time course of effect for local PB delivery was characterized by monitoring the return to baseline seizure activity following local PB infusions.

[0090] EEG activity was recorded for at least 3 hours prior to treatment and for 3-5 hours immediately following treatment to evaluate the effect of ASMs on SLE incidence over time. hTe frequency of seizure-like events (SLEs) in the EEG w as recorded from individual mice 3 hours before drug treatment and up to 4 hours after local administration of 0.4 pg phenobarbital (PB). The average SLE rate was also recorded from the whole group of epileptic mice during the 3-hour baseline period and for the 4 hours following local PB administration. Local delivery of0.017 mg / kg (0.4 pg) PB through the MINI device significantly reduced the number of SLEs at 1 and 2 hours post treatment compared to baseline (FIGS. 11A-11B). At 3 hours post treatment all mice returned to their baseline SLE rates. Local delivery of vehicle had no effect on the number of SLEs compared to baseline (FIG. 11C-11D).

[0091] The frequency of seizure-like events (SLEs) in the EEG was also recorded from individual mice 3 hours before drug treatment and up to 5 hours after systemic administration of 60 mg / kg phenobarbital (PB), in addition to the average SLE rate from the whole group of epileptic mice during the 3-hour baseline period and for the 5 hours following systemic PB administration. Systemic delivery of 60 mg / kg PB also caused a significant reduction in the number of SLEs at 1 and 2 hours post treatment compared to baseline (FIGS. 12A-12B). The number of SLEs also returned to baseline values at 3 hours post treatment, although only 2 / 5 mice returned to their individual baseline SLE rates at this time. The remaining three mice returned to their individual baseline SLE rates at 4 hours post treatment. Systemic delivery of vehicle had no effect on the number of SLEs compared to baseline (FIGS. 12C-12D).EMBODIMENTS

[0092] Some embodiments of the present disclosure can be described in view of one or more of the following:

[0093] Embodiment 1. A method of treating epilepsy in a patient, the method comprising: implanting a micro-invasive neural infusion device at least partially within at least one selected micro-region within the patient’s brain; locally administering, via the implanted micro-invasive neural infusion device, an anti-seizure medication directly into the at least one selected microregion within the patient’s brain; wherein the local administration of the anti-seizure medication directly into the at least one selected micro-region within the patient’s brain is effective to treat the epilepsy while substantially avoiding adverse side effects in the patient that would be observed with systemic administration of the medication at a therapeutically effective systemic dose.

[0094] Embodiment 2. The method of Embodiment 1, wherein the anti-seizure medication is at least one of phenobarbital or valproate.

[0095] Embodiment 3. The method of Embodiment I or 2, wherein the patient has been diagnosed with focal epilepsy or particularly refractory epilepsy.

[0096] Embodiment 4. The method of any one of Embodiments 1 to 3, wherein the therapeutically effective dose is less than 0.05 mg / kg.

[0097] Embodiment 5. The method of Embodiment 4, wherein the therapeutically effective dose is from about 0.004 mg / kg to 0.017 mg / kg.

[0098] Embodiment 6. The method of any one of Embodiments 1 to 5, wherein the local administration of the anti-seizure medication produces a reduced frequency and / or duration of seizures.

[0099] Embodiment 7. The method of any one of Embodiments 1 to 6, where the at least one selected micro-region within the brain is within the temporal lobe or the frontal lobe.

[0100] Embodiment 8. The method of any one of Embodiments 1 to 7, wherein the at least one selected micro-region within the brain is an identified epileptic focus.

[0101] Embodiment 9. The method of any one of Embodiments 1 to 8, wherein the micro- invasive neural infusion device is a microfluidic pump system.

[0102] Embodiment 10. The method of Embodiment 9, wherein the micro-invasive neural infusion device comprises: a device body; a capillary; a fluid source containing a liquid form of the anti-seizure medication; and a microfluidic pump; wherein the device body defines a fluid flow path extending between the capillary and the fluid source, wherein the microfluidic pump is positioned along the fluid flow path so as to control delivery' of the anti-seizure medication from the device, and wherein the capillary comprises a distal end to be placed within the at least one selected micro-region within the brain.

[0103] Embodiment 11. The method of Embodiment 10, wherein the capillary further comprises a bead to be placed within the at least one selected micro-region within the brain to effectuate controlled delivery of the anti-seizure medication to the patient.

[0104] Embodiment 12. The method of Embodiment 10 or 11, wherein the distal end of the capillary is placed within or adjacent an identified epileptic focus.

[0105] Embodiment 13. The method of any one of Embodiments 1 to 12, wherein the local administration is carried out continually or continuously over an extended period of time via the micro-invasive neural infusion device implanted in the patient.

[0106] Embodiment 14. A method of treating a neurological disorder in a patient, the method comprising: identifying a micro-region within the patient’s brain as a source of the neurological disorder; implanting a micro-invasive neural infusion device within the identified micro-region within the patient’s brain, wherein the micro-invasive neural infusion device is a microfluidic pump system; and locally administering less than 0.05 mg / kg of a therapeutic agent, via the micro-invasive neural infusion device directly to the identified micro-region within the patient’s brain, wherein the local administration of less than 0.05 mg / kg of the therapeutic agent is effective to treat the neurological disorder while substantially avoiding adverse side effects in the patient that would be observed with systemic administration of the medication at a therapeutically effective systemic dose.

[0107] Embodiment 15. The method of Embodiment 14, wherein neurological disorder is epilepsy.

[0108] Embodiment 16. The method of Embodiment 14 or 15, wherein the patient has been diagnosed with focal epilepsy or particularly refractory epilepsy.

[0109] Embodiment 17. The method of any one of Embodiments 14 to 16, wherein the therapeutic agent is an anti-seizure medication, such as phenobarbital and / or valproate.

[0110] Embodiment 18. The method of any one of Embodiments 14 to 17, wherein the local administration is carried out continually or continuously over an extended period of time via the micro-invasive neural infusion device implanted in the patient. [OHl] Embodiment 19. The method of any one of Embodiments 14 to 18, wherein the micro-region is an identified epileptic focus.

[0112] Embodiment 20. The method of any one of Embodiments 14 to 19, wherein the local administration of the anti-seizure medication produces a reduced frequency and / or duration of seizures.

Claims

CLAIMSThat which is claimed is:

1. A method of treating epilepsy in a patient, the method comprising: implanting a micro-invasive neural infusion device at least partially within at least one selected micro-region within the patient’s brain; locally administering, via the implanted micro-invasive neural infusion device, an anti-seizure medication directly into the at least one selected micro-region within the patient's brain; wherein the local administration of the anti-seizure medication directly into the at least one selected micro-region within the patient’s brain is effective to treat the epilepsy while substantially avoiding adverse side effects in the patient that w ould be observed with systemic administration of the medication at a therapeutically effective systemic dose.

2. The method of claim 1, wherein the anti-seizure medication is at least one of phenobarbital or valproate.

3. The method of claim 1, w herein the patient has been diagnosed with focal epilepsy or particularly refractory epilepsy.

4. The method of claim 1, wherein the therapeutically effective dose is less than 0.05 mg / kg.

5. The method of claim 4, wherein the therapeutically effective dose is from about 0.004 mg / kg to 0.017 mg / kg.

6. The method of claim 1, wherein the local administration of the anti-seizure medication produces a reduced frequency and / or duration of seizures.

7. The method of claim 1, where the at least one selected micro-region within the brain is within the temporal lobe or the frontal lobe.

8. The method of claim 7, wherein the at least one selected micro-region within the brain is an identified epileptic focus.

9. The method of any one of claims 1 to 8, wherein the micro-invasive neural infusion device is a microfluidic pump system.

10. The method of claim 9, wherein the micro-invasive neural infusion device comprises: a device body; a capillary; a fluid source containing a liquid form of the anti-seizure medication; and a microfluidic pump; wherein the device body defines a fluid flow path extending between the capillary and the fluid source, wherein the microfluidic pump is positioned along the fluid flow path so as to control deliver^' of the anti-seizure medication from the device, and wherein the capillary comprises a distal end to be placed within the at least one selected micro-region within the brain.

11. The method of claim 11 , wherein the capillary further comprises a bead to be placed within the at least one selected micro-region within the brain to effectuate controlled delivery of the anti-seizure medication to the patient.

12. The method of claim 10, wherein the distal end of the capillary is placed within or adjacent an identified epileptic focus.

13. The method of claim 1, wherein the local administration is carried out continually or continuously over an extended period of time via the micro-invasive neural infusion device implanted in the patient.

14. A method of treating a neurological disorder in a patient, the method comprising: identifying a micro-region within the patient’s brain as a source of the neurological disorder; implanting a micro-invasive neural infusion device within the identified microregion within the patient’s brain, wherein the micro-invasive neural infusion device is a microfluidic pump system; and locally administering less than 0.05 mg / kg of a therapeutic agent, via the micro- invasive neural infusion device directly to the identified micro-region 'ithin the patient’s brain.wherein the local administration of less than 0.05 mg / kg of the therapeutic agent is effective to treat the neurological disorder while substantially avoiding adverse side effects in the patient that would be observed with systemic administration of the medication at a therapeutically effective systemic dose.

15. The method of claim 14. wherein neurological disorder is epilepsy.

16. The method of claim 15, wherein the patient has been diagnosed with focal epilepsy or particularly refractory epilepsy.

17. The method of claim 14, wherein the therapeutic agent is an anti-seizure medication, such as phenobarbital and / or valproate.

18. The method of claim 14, wherein the local administration is carried out continually or continuously over an extended period of time via the micro-invasive neural infusion device implanted in the patient.

19. The method of claim 14, wherein the micro-region is an identified epileptic focus.

20. The method of claim 14, wherein the local administration of the anti-seizure medication produces a reduced frequency and / or duration of seizures.

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