Cortical excitability in refractory focal epilepsy treated with novel gene therapy and conventional resective surgery

新型基因疗法和传统切除手术治疗难治性局灶性癫痫的皮质兴奋性

• 批准号: MR/V037579/1
• 负责人: Fahmida Chowdhury
• 金额: $ 16.91万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV037579%2F1
• 关键词: Cortical; excitability; refractory; focal; epilepsy

Epilepsy is one of the most common neurological conditions, and affects around 50 million people worldwide. It is caused by increased excitability of the brain. Patients with epilepsy have recurrent seizures. Unfortunately about a third of patients have ongoing seizures despite taking the many anti-epileptic medications available. Seizures have risks that commonly include injuries but also rarely can result in fatality due to effects of the seizures on breathing and heart rate (known as Sudden Unexpected Death in Epilepsy). In some of these patients, an operation to remove the part of the brain that is causing the seizures, can help to cure seizures. However, there are risks of surgery, especially if the seizures start in or near parts of the brain that are vital for important functions, for example, movement, language or memory function. Another exciting possible new treatment is gene therapy, where a gene is introduced into the brain using a virus as a carrier. In our research institution at UCL, we have developed a gene therapy that works well to control seizures in rats with epilepsy. The next step is to test if this treatment also works in humans. There is a plan to start a clinical trial using a trial of gene therapy as a novel therapy for our patients who would normally be considered for epilepsy surgery. Transcranial magnetic stimulation is useful and safe tool that uses a magnet held over the head to stimulate nerves in the brain and the response can be measured using recording electrodes on the muscles of the hand or by measuring brainwaves on the scalp. It is ideal for studying brain activity in patients with epilepsy, as it can directly probe the workings of brain circuits and give us measures of brain excitability. In this study we plan to use transcranial magnetic stimulation to measure brain activity in patients with focal epilepsy, who are still having seizures, even though they are taking regular anti-epileptic medications. These patients will be treated with either the new gene therapy or the already established treatment of epilepsy surgery. We will take brain excitability measures before and after these treatments. This will help to improve our understanding of this type of epilepsy, and how brain excitability changes in these patients, compared to healthy people. In addition it will also help us understand how both these treatments affect brain excitability. In particular this will give us an insight into the effects of the new gene therapy treatment on the brain. The information we get from this study, will help us understand why some people may become seizure free with either of these treatments whereas others might not. In turn we envisage that, in future, this will help us to predict which patients will benefit most from either treatment. This will allow us to choose the best treatment for patients and improve their seizures and thereby their quality of life.

癫痫是最常见的神经系统疾病之一，影响着全世界约5000万人。它是由大脑兴奋性增强引起的。癫痫患者会反复发作。不幸的是，尽管服用了许多抗癫痫药物，仍有大约三分之一的患者持续发作。癫痫发作的风险通常包括伤害，但由于癫痫发作对呼吸和心率的影响（称为癫痫猝死），很少会导致死亡。对于其中一些患者，通过手术切除导致癫痫发作的大脑部分，可以帮助治愈癫痫发作。然而，手术是有风险的，特别是如果癫痫发作发生在大脑中对运动、语言或记忆功能等重要功能至关重要的部位或附近。另一种令人兴奋的可能的新疗法是基因疗法，即用病毒作为载体将基因引入大脑。在我们伦敦大学学院的研究机构，我们开发了一种基因疗法，可以很好地控制癫痫大鼠的癫痫发作。下一步是测试这种治疗方法是否也适用于人类。我们计划开展一项临床试验，将基因疗法作为一种新疗法，用于治疗那些通常会被考虑进行癫痫手术的患者。经颅磁刺激是一种有用且安全的工具，它使用头顶的磁铁来刺激大脑中的神经，反应可以通过在手肌肉上的记录电极或测量头皮上的脑电波来测量。它是研究癫痫患者大脑活动的理想选择，因为它可以直接探测大脑回路的运作，并为我们提供大脑兴奋性的测量。在这项研究中，我们计划使用经颅磁刺激来测量局灶性癫痫患者的大脑活动，即使他们正在服用常规抗癫痫药物，但仍有癫痫发作。这些患者将接受新的基因疗法或已经建立的癫痫手术治疗。我们将在这些治疗前后测量大脑兴奋性。这将有助于提高我们对这类癫痫的理解，以及与健康人相比，这些患者的大脑兴奋性是如何变化的。此外，它还将帮助我们了解这两种治疗方法是如何影响大脑兴奋性的。特别是，这将使我们深入了解新的基因疗法对大脑的影响。我们从这项研究中得到的信息，将帮助我们理解为什么有些人可以通过这两种治疗而另一些人却不能。反过来，我们设想，在未来，这将帮助我们预测哪些患者将从两种治疗中获益最多。这将使我们能够为患者选择最好的治疗方法，改善他们的癫痫发作，从而改善他们的生活质量。

项目成果

Normative brain mapping of interictal intracranial EEG to localize epileptogenic tissue.

颅内内部脑外的规范性脑作图，以定位癫痫组织。

• DOI: 10.1093/brain/awab380
• 发表时间: 2022-04-29
• 期刊: Brain : a journal of neurology

Probabilistic landscape of seizure semiology localizing values.

• DOI: 10.1093/braincomms/fcac130
• 发表时间: 2022
• 期刊: BRAIN COMMUNICATIONS
• 影响因子: 4.8
• 作者: Alim-Marvasti, Ali;Romagnoli, Gloria;Dahele, Karan;Modarres, Hadi;Perez-Garcia, Fernando;Sparks, Rachel;Ourselin, Sebastien;Clarkson, Matthew J.;Chowdhury, Fahmida;Diehl, Beate;Duncan, John S.
• 通讯作者: Duncan, John S.

Multiple mechanisms shape the relationship between pathway and duration of focal seizures.

• DOI: 10.1093/braincomms/fcac173
• 发表时间: 2022
• 期刊: Brain communications
• 影响因子: 4.8