Precise, non-invasive, axon-sparing surgery for the treatment of drug resistant epilepsy

精确、非侵入性、保留轴突的手术治疗耐药性癫痫

• 批准号: 9894855
• 负责人: KEVIN Scott LEE
• 金额: $ 41.19万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894855
• 关键词: Ablation; Affect; Animals; Antiepileptic Agents; Area; Axon; Blood - brain barrier anatomy; Blood coagulation; Brain; Brain region; Cells; Chronic; Communities; Corpus Callosum; Cortical Dysplasia; Data; Economics; Edema; Environment; Epilepsy; Excision; Exhibits; Face; Fiber; Focused Ultrasound; Focused Ultrasound Therapy; Glutamates; Goals; Hemorrhage; Individual; Infection; Injections; Intervention; Intractable Epilepsy; Lesion; Life; Long-Term Effects; Magnetic Resonance; Medical; Modality; Modeling; Nervous System Physiology; Neurologic Deficit; Neurological outcome; Neurological status; Neurons; Neurotoxins; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Permeability; Pharmacology; Play; Procedures; Quality of life; Quinolinic Acid; Recurrence; Risk; Rodent Model; Role; Seizures; Stroke; Structure; Surgical complication; System; Techniques; Temporal Lobe; Testing; Therapeutic; Tissues; World Health Organization; acronyms; brain circuitry; brain dysfunction; brain parenchyma; dosage; functional outcomes; gray matter; improved; minimally invasive; nervous system disorder; neurosurgery; neurotoxic; novel; novel strategies; preservation; side effect; uptake; white matter

Project Summary: Drug resistant epilepsy (DRE) remains a difficult biomedical challenge, affecting approximately one-third of newly-treated cases of epilepsy. Individuals impacted by DRE endure a poor quality of life, and can face life-threatening complications. Surgical removal of epileptogenic tissue can dramatically reduce seizures and improve quality of life. However, epilepsy surgery can be highly invasive, may produce damage that is not restricted to the target tissue, and is not feasible in certain critical areas of the brain. Also, surgical damage that is not conformal to its target and affects neighboring, eloquent tissue can produce long- term functional deficits. Finally, incomplete resection or ablation of target tissue can result in poor seizure management. The purpose of this proposal is to develop and test a non-invasive, targeted, conformal surgical strategy that will optimize seizure control, expand the types of epilepsies amenable to surgical intervention, and, ultimately, improve the quality of life of patients with DRE. This project will utilize Magnetic Resonance- guided, low-intensity Focused Ultrasound (MRg-FUS) to focally and reversibly open the blood brain barrier (BBB) in a targeted manner without producing a thermal lesion. Transient opening of the BBB allows timed delivery of an otherwise BBB-impermeable neurotoxin to the brain parenchyma in order to produce a focal, axon-sparing lesion of targeted neurons. The neurotoxin Quinolinic Acid (QA) is well tolerated when administered systemically at high dosages, exhibits little or no permeability through the intact BBB, is relatively unaffected by glutamatergic uptake systems in the brain parenchyma, and is capable of producing axon- sparing lesions. We present here the first evidence that systemically-administered QA combined with MRgFUS produces focal neuronal damage, while sparing axons in precisely targeted regions of the brain. Moreover, this approach affords the opportunity to treat targets that would be difficult, if not impossible, to treat using currently-available surgical techniques. Finally, these outcomes can be achieved while simultaneously limiting the risks of collateral damage, surgical side effects, and long-term neurological deficits. The current project will develop and test this novel approach for limiting seizures using a model of limbic epilepsy. The guiding hypothesis is that targeted disconnection of dysfunctional brain circuitry can be achieved in a precise, conformal, and non-invasive manner, and that this strategy can be implemented to control seizures and improve neurological outcomes. This approach provides distinct advantages over current surgical modalities as it will restrict the extent of tissue damage, allow treatment of regions that are otherwise inaccessible, reduce peri-surgical complications, mitigate against long-term functional deficits, and do all of this in a non-invasive manner. Notably, this strategy could prove useful for treating a variety of neurological disorders in which disturbances in connectivity play a role.

项目概要： 耐药性癫痫（DRE）仍然是一个困难的生物医学挑战， 大约三分之一的新治疗的癫痫病例。受焚毁去除率影响的个人承受的质量很差 可能会面临危及生命的并发症。手术切除致痫组织可以显著地 减少癫痫发作，提高生活质量。然而，癫痫手术可以是高度侵入性的，可能会产生 不限于靶组织的损伤，并且在大脑的某些关键区域不可行。还有， 与其目标不共形并影响邻近功能组织的手术损伤可产生长期的 长期功能缺陷。最后，靶组织的不完全切除或消融可导致癫痫发作不良 管理该提案的目的是开发和测试一种非侵入性，靶向，适形手术 战略，将优化癫痫控制，扩大类型的癫痫服从手术干预， 并最终改善DRE患者的生活质量。该项目将利用磁共振- 引导的低强度聚焦超声（MRg-FUS）局部可逆性打开血脑屏障 (BBB)而不产生热损伤。BBB的瞬时打开允许定时的 将另外的BBB-不可渗透的神经毒素递送至脑实质以产生局灶性， 靶神经元的轴突保留病变。神经毒素喹啉酸（QA）耐受良好， 以高剂量全身给药，表现出很少或没有通过完整BBB的渗透性， 不受脑实质中的神经递质摄取系统的影响，并且能够产生轴突， 避免损伤。我们在这里提出了系统性QA与MRgFUS相结合的第一个证据 产生局灶性神经元损伤，同时在大脑的精确目标区域保留轴突。而且这 这种方法提供了治疗靶点的机会，这些靶点很难（如果不是不可能的话）用 目前可用的外科技术。最后，这些结果可以实现，同时限制 附带损伤、手术副作用和长期神经功能缺损的风险。目前的项目将 开发和测试这种新的方法，用于限制癫痫发作使用边缘癫痫模型。的指导 有一种假设是， 适形、非侵入性的方式，并且可以实施这种策略来控制癫痫发作， 改善神经系统结果。这种方法提供了优于当前手术方式的明显优势， 它将限制组织损伤的程度，允许治疗否则无法到达的区域， 围手术期并发症，减轻长期功能缺陷，并在非侵入性 方式值得注意的是，这种策略可以证明对治疗各种神经系统疾病是有用的， 连接性干扰也发挥了作用。