Supplementary Material for: Cavernous Malformation Hemorrhagic Presentation at Diagnosis Associated with Low 25-Hydroxy-Vitamin D Level

Background: Cavernous malformations (CM) are angiographically occult vascular malformations that may be incidental or present with intracerebral or spinal hemorrhage, seizures, or nonhemorrhagic focal neurologic deficit (FND). Recently in vitro data have suggested vitamin D may play a role in stabilizing CCM2 endothelial cells. Little is known about the effect of vitamin D in human CM disease. Methods: Beginning in 2015, consecutive patients at our institution with radiologically confirmed CM were recruited to participate in a prospective clinical registry as well as 25-hydroxy-vitamin D study. A structured interview, survey, and examination were performed at baseline. Medical records and magnetic resonance imaging studies were reviewed and data collected included comorbid conditions, medication use, and location of CM. Standard definition of clinical hemorrhage, FND, and seizures was used. Univariate and multivariate logistic regression models were used, and OR, 95% CIs, and likelihood-ratio p values were calculated to determine the influence of the 25-hydroxy-vitamin D level on clinical presentation with hemorrhage. Results: Of 213 patients enrolled in the clinical registry between January 2015 and October 2018, 70 participated in the vitamin D study (median age: 38.3 years; 51.4% female). Of the 70 participants, 30 (42.9%) presented with hemorrhage. 25-Hydroxy-vitamin D levels were performed within 1 year of symptoms in 64.1% of patients. Patients presenting with hemorrhage had a lower 25-hydroxy-vitamin D level compared to those presenting with seizure without hemorrhage, FND, or as an incidental finding (median 25.5 ng/mL; range 11–59 hemorrhage vs. median 31.0; range 14–60, no hemorrhage; p = 0.04). After adjusting for age, month of blood draw, and body mass index, 25-hydroxy-vitamin D remained a significant predictor of hemorrhagic presentation. Brainstem location also predicted hemorrhage at presentation. Conclusion: Low 25-hydroxy-vitamin D level was more common in patients with CM presenting with hemorrhage. This study supports the potential role of modifiable factor in the initial clinical presentation of CM. Further study is needed to determine the role of vitamin D on prospective hemorrhage risk and whether supplementation may be beneficial.

背景：海绵状血管畸形（Cavernous malformations, CM）是血管造影隐匿性血管畸形，可偶然发现，或表现为脑内或脊髓出血、癫痫发作，或非出血性局灶性神经功能缺损（FND）。近期体外研究数据表明，维生素D可能在稳定CCM2内皮细胞中发挥作用，但目前关于维生素D对人类CM疾病的影响尚不清楚。
方法：自2015年起，本机构连续招募经影像学确诊为CM的患者，纳入前瞻性临床注册研究及25-羟基维生素D（25-hydroxy-vitamin D）研究。在基线时对受试者进行结构化访谈、问卷调查及体格检查。回顾患者的病历资料与磁共振成像（magnetic resonance imaging, MRI）结果，收集的信息包括合并症、用药情况及CM的病变部位。采用临床出血、FND及癫痫发作的标准定义。使用单因素及多因素logistic回归模型，计算比值比（OR）、95%置信区间（CI）及似然比p值，以明确25-羟基维生素D水平对以出血为首发临床表现的影响。
结果：2015年1月至2018年10月期间，共213名患者纳入临床注册研究，其中70名参与了维生素D研究（中位年龄38.3岁；女性占比51.4%）。70名受试者中，30名（42.9%）以出血为首发临床表现。64.1%的患者在症状出现1年内完成了25-羟基维生素D水平检测。以出血为首发表现的患者，其25-羟基维生素D水平低于以无出血性癫痫发作、FND或偶然发现为首发表现的患者（出血组中位值25.5 ng/mL，范围11~59；非出血组中位值31.0 ng/mL，范围14~60；p=0.04）。在校正年龄、采血月份及体质量指数后，25-羟基维生素D仍为出血性首发表现的显著预测因素。病变位于脑干也可预测首发时出现出血。
结论：以出血为首发临床表现的CM患者中，低25-羟基维生素D水平更为常见。本研究支持可干预因素在CM初始临床表现中发挥潜在作用。未来仍需进一步研究明确维生素D对远期出血风险的影响，以及补充维生素D是否具有临床获益。