Imaging the effect of centrotemporal spikes and seizures on language in children

描述（由申请人提供）：良性儿童癫痫伴中央颞叶尖峰（BECTS）是一种极为常见的儿童癫痫类型，传统上认为其病程为良性，但最近的研究表明，BECTS患者的认知功能，特别是语言功能经常受损。然而，尚不清楚癫痫发作、中央颞叶尖峰（CTS）或其他因素是否会导致可能影响学习表现和社会互动的负面认知后果。BECTS患者有分散的癫痫发作，但非常频繁的CTS，并可能患有未确诊的认知和语言缺陷。这表明CTS的因果作用尚未得到详细调查。该项目将研究癫痫发作和CTS对BECTS患者在诊断时和一年后神经认知功能的影响。我们将收集有关抗癫痫药物左乙拉西坦对CTS影响的关键信息，这将为未来旨在消除CTS和改善长期预后的III期临床试验提供信息。本研究将利用语言功能磁共振成像来探索CTS、癫痫发作和神经心理结果之间的相互作用，以破译BECTS儿童语言缺陷背后的神经回路变化。在诊断时使用标准化的神经心理学测试和功能磁共振成像，本研究将首先描述BECTS儿童语言问题的性质和发生率，分离CTS和癫痫发作的影响。有BECTS的儿童在语言技能测试中的表现低于规范标准，并伴随着功能磁共振成像测试中支持语言处理的神经回路异常。这些数据还可以通过考虑诸如癫痫发作次数、发病年龄、CTS的频率和偏侧性等因素，来确定哪些患有BECTS的儿童最容易出现语言问题。该探索性临床试验还将为正确设计和开展未来的双盲III期随机临床试验（RCT）提供关键信息，该试验旨在通过消除CTS来改善儿童的语言预后。采用开放标签剂量范围选择设计和1年随访，我们将确定哪一剂量的左乙拉西坦控制癫痫发作，消除CTS是耐受性良好的，应该在III期试验中使用。与对照组相比，我们还将通过1年随访神经心理测试和功能磁共振成像（fMRI）检查接受lev治疗和未接受lev治疗的BECTS儿童的语言功能和语言神经回路的变化程度（这将记录未接受lev治疗的BECTS儿童神经心理功能的自然历史，并提供有关左乙西坦效果的额外信息）。未来的双盲随机对照试验将比较左乙拉西坦和卡马西平（目前的治疗标准，不能消除CTS）在BECTS中的应用。这项未来的研究将通过证明所有BECTS儿童需要AED治疗来消除CTS，从而改善长期语言和认知结果，从而改变临床实践。

DESCRIPTION (provided by applicant): Benign Childhood Epilepsy with CentroTemporal Spikes (BECTS), an extremely common type of childhood epilepsy, is traditionally assumed to have a benign course, but recent studies have shown that cognitive function, especially language, is often impaired in BECTS patients. However, it is not clear whether the seizures, the centrotemporal spikes (CTS), or other factors cause the negative cognitive consequences that may impact school performance and social interaction. BECTS patients have scattered seizures but very frequent CTS, and may be suffering with undiagnosed cognitive and language deficits. This suggests a causal role for CTS that has not yet been investigated in detail. This project will examine the impact of seizures and CTS on neurocognitive function in BECTS patients, at diagnosis and after one year. We will gather critical information regarding the effect of the antiepileptic medication levetiracetam on CTS, which will inform a future Phase III clinical trial aimed at eliminating CTS and improving long term outcome. This study will explore the interactions between CTS, seizures and neuropsychological outcomes using Functional MRI of language in order to decipher changes in neural circuitry that underlie language deficits found in children with BECTS. Using standardized neuropsychological testing and fMRI at the time of diagnosis, this study will first characterize the nature and incidence of language problems in children with BECTS, separating the effects of CTS and seizures. It is expected that children with BECTS will perform below normative standards on tests of language skill, accompanied by aberrations in the neural circuitry supporting language processing as tested with fMRI. These data will also make it possible to characterize which children with BECTS are most at risk for language problems, by taking into account contributing factors such as number of seizures, age of onset, and frequency and lateralization of CTS. The proposed exploratory clinical trial will also provide key information needed to properly design and conduct a future double blind Phase III randomized clinical trial (RCT) children aimed at improving language outcome through elimination of CTS. Using an open-label dose-ranging selection design and 1-year follow up, we will determine which dose of levetiracetam control seizures, eliminate CTS is well tolerated and should be used in the Phase III trial. We will also examine the extent of changes in language function and neural circuitry of language with 1-year follow-up neuropsychological testing and fMRI in LEV-treated and untreated BECTS compared to controls (which will document the natural history of neuropsychological function in untreated BECTS children and give additional information about the effect of levetiracetam). The future double blind RCT will compare levetiracetam to carbamazepine (the current standard of care that does not eliminate CTS) in BECTS. This future study would change clinical practice by demonstrating the need for AED treatment in all BECTS children to eliminate CTS, in turn improving long term language and cognitive outcome. PUBLIC HEALTH RELEVANCE: This project examines how seizures, and abnormal brain activity, affect language skill in children with Benign Childhood Epilepsy with Centro-Temporal Spikes (BECTS). BECTS is a common type of childhood epilepsy, and while BECTS patients stop having seizures by their late teenage years, many studies have shown that these children have language problems that may lead to academic and social difficulties. Using standardized language testing, monitoring of brain activity, and MRI brain imaging, this project aims to determine what particular combination of BECTS symptoms put children most at risk for language problems and what dose of the anti-epileptic medication levetiracetam may be helpful. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.