See related article, p 3532

Epilepsy after pediatric stroke is associated with worse functional outcome¹ and poorer health status.² An estimated 30% of children develop epilepsy during the first decade after pediatric stroke,^3,4 but measurements of epilepsy incidence beyond this period have been limited to smaller studies and frequently have insufficient data to provide families and health care professionals with accurate information.

In this issue of Stroke, Sundelin et al⁵ report a retrospective study of epilepsy incidence rates after pediatric ischemic stroke using data from the population-based health registers in Sweden from over 4 decades (1969–2016). The study identified 1220 cases of pediatric stroke from birth, death, and patient health registers who together had a median follow-up of 8.7 years. The study also identified 12 155 matched controls with 11.8 years of follow-up from the Swedish Total Population register for comparison. Those with perinatal ischemic stroke had an epilepsy incidence rate of 27.2 per 1000 person-years. Children who had a stroke after the perinatal period had an epilepsy incidence rate of 11.6 per 1000 person-years. Capitalizing on the long study period, the authors measured a 26% cumulative risk of epilepsy by 30 years poststroke.

Epilepsy risk was greatest in the first 6 months after stroke (hazard ratio 119) and remained elevated above the general population over the following decades. Twenty years after a pediatric stroke, the risk of developing new-onset epilepsy was elevated nearly 8-fold compared with the general population. The delayed onset of poststroke epilepsy presents an opportunity to intervene if future antiepileptogenic therapeutics are identified.

While smaller prior studies of pediatric stroke have estimated incidence rates and predictors of poststroke epilepsy,^3,4,6 this relatively large study provides more precise estimates and also measured epilepsy risk among relatives using the Swedish Multi-Generation register. The contribution of genetic factors to epileptogenesis after a brain injury has been debated for many years. Several studies suggest evidence for a familial vulnerability to epilepsy acquired after traumatic brain injury⁷ or stroke in adults,⁸ but most have had limited power to detect an association. Sundelin et al found that parents of pediatric stroke patients were 40% more likely and siblings were 60% more likely to have a diagnosis of epilepsy. The association was found among first-degree relatives of pediatric stroke patients who developed epilepsy and those who remained seizure free, suggesting that the increased risk for epilepsy among relatives correlates with the risk of stroke itself. This finding challenges the assumption that epilepsy is solely symptomatic and acquired in pediatric stroke patients and instead suggests a joint genetic vulnerability to both stroke and epilepsy. Prior large-scale genetic studies such as the Brainstorm study previously suggested genetic overlap between various brain diseases explained by common genetic factors.⁹ The authors’ finding in the current study may support this observation.

The study findings should be interpreted cautiously. Nongenetic social factors could explain an increased rate of diagnosing epilepsy in relatives. After a child has a stroke, it is possible that family members are more attuned to new neurological events and more connected to medical care, thereby increasing the likelihood of an epilepsy diagnosis. A second possibility is that shared genetic risk is due to rare monogenic conditions such as metabolic or mitochondrial disorders or inherited autoimmune or inflammatory disease. Identifying these disorders and their genetic underpinnings may lead to treatments that decrease risk of both epilepsy and early stroke in affected families. Knowledge about the genetic basis of human epilepsy and putative precision medicine treatments is growing exponentially.¹⁰ This progress will continue to expand to related areas like pediatric stroke. Pursuing further research on poststroke epilepsy and potential genetic contributions is relevant to patient care, will increase our broader understanding of acquired epilepsies, and may lead to exciting medical breakthroughs for rare genetic diseases.

Disclosures Dr Helbig is a consultant for Biogen, Inc (unrelated to current work); Patent—WO2020227406 Micro-RNA site-blocking oligonucleotides to treat epileptic encephalopathy (unrelated to current work). Dr Fox is an independent contractor for Data Safety Monitoring Board for National Institutes of Health (unrelated to current work); Grants—American Heart Association (unrelated to current work), National Institutes of Health (topically related), and Pediatric Epilepsy Research Foundation (topically related).

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

For Disclosures, see page 3542.

参见相关文章，第 3532 页

小儿卒中后癫痫与较差的功能结果¹和较差的健康状况相关。²估计有 30% 的儿童在小儿卒中后的第一个十年内发展为癫痫，^3,4但在此期间之后癫痫发病率的测量仅限于较小的研究，并且通常没有足够的数据为家庭和医疗保健专业人员提供准确的信息。

在本期Stroke 中，Sundelin 等人⁵报告使用瑞典 40 多年（1969-2016 年）基于人群的健康登记数据的儿童缺血性卒中后癫痫发病率的回顾性研究。该研究从出生、死亡和患者健康登记册中确定了 1220 例小儿中风病例，这些病例的中位随访时间为 8.7 年。该研究还从瑞典总人口登记册中确定了 12155 名匹配的对照，随访时间为 11.8 年，以进行比较。围产期缺血性卒中患者的癫痫发病率为 27.2/1000 人年。围产期后发生中风的儿童癫痫发病率为每 1000 人年 11.6 例。利用漫长的研究期，作者测量到中风后 30 年癫痫的累积风险为 26%。

中风后的前 6 个月癫痫风险最大（风险比 119），并且在接下来的几十年中一直高于一般人群。儿科卒中发生 20 年后，与普通人群相比，发生新发癫痫的风险增加了近 8 倍。如果确定未来的抗癫痫治疗药物，中风后癫痫的延迟发作为干预提供了机会。

虽然先前较小的儿科卒中研究估计了卒中后癫痫的发病率和预测因素，^3,4,6这项相对较大的研究提供了更精确的估计，并且还使用瑞典多代登记册测量了亲属之间的癫痫风险。多年来，遗传因素对脑损伤后癫痫发生的贡献一直存在争议。几项研究表明，有证据表明，在成人中，外伤性脑损伤⁷或中风后获得的癫痫家族易感性，⁸但大多数人检测关联的能力有限。Sundelin 等人发现，儿科卒中患者的父母被诊断出癫痫的可能性要高 40%，兄弟姐妹被诊断出癫痫的可能性要高 60%。在发生癫痫的儿科卒中患者的一级亲属和没有癫痫发作的儿童中发现了这种关联，这表明亲属中癫痫风险的增加与卒中风险本身相关。这一发现挑战了癫痫仅是小儿中风患者的症状和获得性的假设，相反，这表明中风和癫痫具有共同的遗传易感性。先前的大规模遗传研究，如头脑风暴研究，先前表明，由共同遗传因素解释的各种脑部疾病之间存在遗传重叠。⁹作者在当前研究中的发现可能支持这一观察结果。

应谨慎解释研究结果。非遗传性社会因素可以解释亲属癫痫诊断率增加的原因。孩子中风后，家庭成员可能更适应新的神经系统事件并与医疗保健联系更紧密，从而增加癫痫诊断的可能性。第二种可能性是，共同的遗传风险是由罕见的单基因疾病引起的，例如代谢或线粒体疾病或遗传性自身免疫病或炎症性疾病。确定这些疾病及其遗传基础可能会导致治疗降低受影响家庭的癫痫和早期中风的风险。关于人类癫痫的遗传基础和推定的精准医学治疗的知识呈指数增长。¹⁰这一进展将继续扩展到小儿卒中等相关领域。对中风后癫痫和潜在遗传贡献的进一步研究与患者护理相关，将增加我们对获得性癫痫的更广泛了解，并可能为罕见遗传疾病带来令人兴奋的医学突破。

披露Helbig 博士是 Biogen, Inc 的顾问（与当前工作无关）；专利—WO2020227406 Micro-RNA 位点阻断寡核苷酸治疗癫痫性脑病（与当前工作无关）。Fox 博士是美国国立卫生研究院数据安全监测委员会的独立承包商（与当前工作无关）；资助——美国心脏协会（与当前工作无关）、美国国立卫生研究院（与当前工作相关）和小儿癫痫研究基金会（与当前工作相关）。

本文中表达的观点不一定是编辑或美国心脏协会的观点。

有关披露，请参阅第 3542 页。