Ihnen S Katie Z, Alperin Samuel, Capal Jamie K, Cohen Alexander L, Peters Jurriaan M, Bebin E Martina, Northrup Hope A, Sahin Mustafa, Krueger Darcy A
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Epilepsia. 2025 Jan;66(1):117-133. doi: 10.1111/epi.18172. Epub 2024 Oct 29.
Epilepsy and intellectual disability are common in tuberous sclerosis complex (TSC). Although early life seizures and intellectual disability are known to be correlated in TSC, the differential effects of age at seizure onset and accumulated seizure burden on development remain unclear.
Daily seizure diaries, serial neurodevelopmental testing, and brain magnetic resonance imaging were analyzed for 129 TSC patients followed from 0 to 36 months. We used machine learning to identify subgroups of patients based on neurodevelopmental test scores at 36 months of age and assessed the stability of those subgroups at 12 months. We tested the ability of candidate biomarkers to predict 36-month neurodevelopmental subgroup using univariable and multivariable logistic regression. Candidate biomarkers included age at seizure onset, accumulated seizure burden, tuber volume, sex, and earlier neurodevelopmental test scores.
Patients clustered into two neurodevelopmental subgroups at 36 months of age, higher and lower scoring. Subgroup was mostly (75%) the same at 12 months. Significant univariable effects on subgroup were seen only for accumulated seizure burden (largest effect), earlier test scores, and tuber volume. Neither age at seizure onset nor sex significantly distinguished 36-month subgroups, although for girls but not boys there was a significant effect of age at seizure onset. In the multivariable model, accumulated seizure burden and earlier test scores together predicted 36-month neurodevelopmental group with 82% accuracy and an area under the curve of .86.
These results untangle the contributions of age at seizure onset and accumulated seizure burden to neurodevelopmental outcomes in young children with TSC. Accumulated seizure burden, rather than the age at seizure onset, most accurately predicts neurodevelopmental outcome at 36 months of age. These results emphasize the need to manage seizures aggressively during the first 3 years of life for patients with TSC, not only to promote seizure control but to optimize cognitive function.
癫痫和智力残疾在结节性硬化症（TSC）中很常见。虽然已知TSC患者的早期癫痫发作和智力残疾存在关联，但癫痫发作起始年龄和累积癫痫发作负担对发育的不同影响仍不清楚。
对129例从0至36个月进行随访的TSC患者的每日癫痫发作日记、系列神经发育测试和脑磁共振成像进行分析。我们使用机器学习根据36个月大时的神经发育测试分数识别患者亚组，并在12个月时评估这些亚组的稳定性。我们使用单变量和多变量逻辑回归测试候选生物标志物预测36个月神经发育亚组的能力。候选生物标志物包括癫痫发作起始年龄、累积癫痫发作负担、结节体积、性别和早期神经发育测试分数。
患者在36个月大时分为两个神经发育亚组，得分较高和较低。12个月时亚组大多（75%）相同。仅累积癫痫发作负担（影响最大）、早期测试分数和结节体积对亚组有显著的单变量影响。癫痫发作起始年龄和性别均未显著区分36个月时的亚组，尽管对于女孩而非男孩，癫痫发作起始年龄有显著影响。在多变量模型中，累积癫痫发作负担和早期测试分数共同预测36个月神经发育组的准确率为82%，曲线下面积为0.86。
这些结果阐明了癫痫发作起始年龄和累积癫痫发作负担对TSC幼儿神经发育结局的影响。累积癫痫发作负担而非癫痫发作起始年龄最准确地预测36个月大时的神经发育结局。这些结果强调了对TSC患者在生命的前3年积极控制癫痫发作的必要性，不仅是为了促进癫痫控制，也是为了优化认知功能。
