Proof of Principle for a Diagnostic Blood Test of Recurrent Seizures

描述（由申请人提供）：癫痫是一种严重且昂贵的神经系统疾病，约占美国人口的3%，通常既昂贵又难以诊断。目前，医生的诊断是基于医生的临床印象、脑电图（EEG）、磁共振成像（MRI），以及在可能的情况下，结合闭路电视和脑电图监测的多天住院检查。最近的数据表明，脑炎是复发性癫痫发作的一个关键病理生理因素，我们在这项研究的基础上开发了一种正在申请专利的复发性癫痫发作诊断血液检测：复发性发作事件的中枢神经系统特异性检测（CARPE）。CARPE是独特的，因为它测量了sICAM5（一种抗炎中枢神经系统源蛋白）和TARC（一种淋巴细胞化学吸引剂）的血浆水平，我们发现癫痫患者的浓度一直很高。在宾夕法尼亚大学收集的先期数据中，CARPE血液测试精确地将反复发作的患者与正常对照区分开。[在这里，我们将从宾夕法尼亚癫痫中心的240名新患者中收集样本进行CARPE测试，这些患者将接受诊断检查，包括脑电图检查。经过六个月的临床治疗，一个由三名癫痫学家组成的独立委员会将确定每位患者的诊断。为了确定准确性，我们将通过改变癫痫患者分类的阈值来构建CARPE敏感性和特异性的ROC曲线。金标准组无法得出结论性诊断的患者将被排除在此分析之外，并且曲线下的面积必须显著超过0.7。为了确定在随后的关键研究中使用的阈值，我们将分析整个组，使用金标准小组对诊断不明确的患者的最佳估计。我们的目标是选择CARPE识别癫痫患者的阈值，特异性至少为0.8，敏感性至少为0.8。在研究结束时，我们期望证明CARPE试验诊断癫痫的准确性，并建立诊断阈值。最终，我们希望CARPE测试结果表明癫痫的患者能够放弃额外的癫痫诊断程序。在二期试验中，我们将建议在一项涉及所有年龄组的大量患者的多中心枢纽研究中验证该试验。我们预计这将导致CARPE血液检测作为一种快速、广泛可及且具有成本效益的复发性癫痫发作诊断检测，成功地重新启动510(k)上市前通报和营销。如果成功，CARPE诊断性血液检查将提供一种快速、可获得和具有成本效益的癫痫诊断方法，从而为患者和医学界带来直接和实质性的好处。

DESCRIPTION (provided by applicant): Epilepsy is a serious and costly neurologic condition that affects approximately 3% of the US population, and is often both costly and difficult to diagnose. Presently, a physician's diagnosis is based on a combination of the physician's clinical impression, electroencephalogram (EEG), magnetic resonance imaging (MRI) and, where available, a multiday inpatient test combining closed circuit TV and EEG monitoring. Recent data have established brain inflammation as a critical factor in the pathophysiology of recurrent seizures, and we have built on this research to develop a patent-pending diagnostic blood test for recurrent seizures: CNS-specific Assay for Recurrent Paroxysmal Events (CARPE). CARPE is unique, as it measures plasma levels of sICAM5, an anti-inflammatory CNS origin protein, and TARC, a lymphocyte chemoattractor that we have found in consistently high concentrations in epilepsy patients. In pioneer data collected at the University of Pennsylvania, the CARPE blood test precisely separated patients with recurrent seizures from normal controls. [Here we will collect samples for CARPE testing from a cohort of 240 new patients at the Penn Epilepsy Center who will undergo a diagnostic workup, including an EEG. After six months of clinical care, an independent board of three epileptologists will determine each patient's diagnosis. To determine accuracy, we will construct ROC curves for CARPE's sensitivity and specificity by varying the threshold value for classifying epilepsy patients. Patients for whom the gold standard panel is unable to reach a conclusive diagnosis will be excluded from this analysis, and the area under the curve must significantly exceed 0.7. To determine the threshold values to be used in a subsequent pivotal study, we will analyze the entire group, using the gold standard panel's best estimate for patients with an unclear diagnosis. We aim to choose the threshold value of CARPE for identifying epilepsy patients with specificity of at least 0.8 and sensitivity of at least 0.8. At the conclusion of the study, we expct to demonstrate the accuracy of the CARPE test in diagnosing epilepsy and establish the diagnostic threshold values. Ultimately, we expect that patients whose CARPE test results indicate epilepsy will be able to forgo additional epilepsy diagnostic procedures.] In Phase II we will propose to validate the test in a multi-center pivotal study involving larger numbers of patients of all age groups. We expect this to lead to a successful de novo 510(k) Premarket Notification and marketing of the CARPE blood test as a rapid, widely accessible, and cost-effective diagnostic test for recurrent seizures. If successful, the CARPE diagnostic blood test will provide immediate and substantial benefits to patients and the medical community by offering a rapid, accessible, and cost-effective means of diagnosing epilepsy.