Translational Neuroradiology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
JAMA Neurol. 2019 Dec 1;76(12):1474-1483. doi: 10.1001/jamaneurol.2019.2399.
In multiple sclerosis (MS), chronic active lesions, which previously could only be detected at autopsy, can now be identified on susceptibility-based magnetic resonance imaging (MRI) in vivo as non-gadolinium-enhancing lesions with paramagnetic rims. Pathologically, they feature smoldering inflammatory demyelination at the edge, remyelination failure, and axonal degeneration. To our knowledge, the prospect of long-term in vivo monitoring makes it possible for the first time to determine their contribution to disability and value as a treatment target.
To assess whether rim lesions are associated with patient disability and long-term lesion outcomes.
DESIGN, SETTING, PARTICIPANTS: We performed 3 studies at the National Institutes of Health Clinical Center: (1) a prospective clinical/radiological cohort of 209 patients with MS (diagnosis according to the 2010 McDonald revised MS criteria, age ≥18 years, with 7-T or 3-T susceptibility-based brain MRI results) who were enrolled from January 2012 to March 2018 (of 209, 17 patients [8%] were excluded because of uninterpretable MRI scans); (2) a radiological/pathological analysis of expanding lesions featuring rims; and (3) a retrospective longitudinal radiological study assessing long-term lesion evolution in 23 patients with MS with yearly MRI scans for 10 years or more (earliest scan, 1992).
(1) Identification of chronic rim lesions on 7-T or 3-T susceptibility-based brain MRI in 192 patients with MS and the association of rim counts with clinical disability (primary analysis) and brain volume changes (exploratory analysis). (2) Pathological characterization of 10 expanding lesions from an adult with progressive MS who came to autopsy after 7 years of receiving serial in vivo MRI scans. (3) Evaluation of annual lesion volume change (primary analysis) and T1 times (exploratory analysis) in 27 rim lesions vs 27 rimless lesions.
Of 209 participants, 104 (50%) were women and 32 (15%) were African American. One hundred seventeen patients (56%) had at least 1 rim lesion regardless of prior or ongoing treatment. Further, 84 patients (40%) had no rims (mean [SD] age, 47 [14] years), 66 (32%) had 1 to 3 rims (mean [SD] age, 47 [11] years), and 42 (20%) had 4 rims or more (mean [SD] age, 44 [11] years). Individuals with 4 rim lesions or more reached motor and cognitive disability at an earlier age. Normalized volumes of brain, white matter, and basal ganglia were lower in those with rim lesions. Whereas rimless lesions shrank over time (-3.6%/year), rim lesions were stable in size or expanded (2.2%/year; P < .001). Rim lesions had longer T1 times, suggesting more tissue destruction, than rimless lesions. On histopathological analysis, all 10 rim lesions that expanded in vivo had chronic active inflammation.
Chronic active lesions are common, are associated with more aggressive disease, exert ongoing tissue damage, and occur even in individuals treated with effective disease-modifying therapies. These results prompt the planning of MRI-based clinical trials aimed at treating perilesional chronic inflammation in MS.
在多发性硬化症（MS）中，以前只能在尸检中发现的慢性活动性病变，现在可以在基于敏感性的活体磁共振成像（MRI）上被识别为具有顺磁性边缘的非钆增强病变。从病理学上看，它们的边缘有潜伏性炎症性脱髓鞘，再髓鞘失败和轴突变性。据我们所知，长期的活体监测的前景首次使得确定它们对残疾的贡献和作为治疗靶点的价值成为可能。
评估边缘病变是否与患者的残疾和长期病变结果有关。
设计、地点、参与者：我们在国立卫生研究院临床中心进行了三项研究：（1）一项前瞻性临床/放射学队列研究，共纳入 209 例 MS 患者（根据 2010 年麦克唐纳修订后的 MS 标准诊断，年龄≥18 岁，有 7-T 或 3-T 基于敏感性的脑 MRI 结果），于 2012 年 1 月至 2018 年 3 月间入组（209 例患者中，有 17 例[8%]因 MRI 扫描无法解读而被排除）；（2）一项对具有边缘的扩展病变的放射学/病理学分析；（3）一项对 23 例 MS 患者进行的回顾性纵向放射学研究，这些患者每年进行 MRI 扫描，持续 10 年或以上（最早的扫描时间为 1992 年）。
（1）在 192 例 MS 患者的 7-T 或 3-T 基于敏感性的脑 MRI 上识别出慢性边缘病变，并将边缘计数与临床残疾（主要分析）和脑容量变化（探索性分析）相关联。（2）对一名接受了连续活体 MRI 扫描 7 年，后来接受尸检的进展性 MS 成年患者的 10 个扩展病变进行病理学特征描述。（3）评估 27 个边缘病变与 27 个无边缘病变的每年病变体积变化（主要分析）和 T1 时间（探索性分析）。
在 209 名参与者中，有 104 名（50%）为女性，32 名（15%）为非裔美国人。117 名患者（56%）无论是否接受过治疗，都至少有 1 个边缘病变。进一步地，84 名患者（40%）没有边缘病变（平均[SD]年龄，47[14]岁），66 名（32%）有 1 至 3 个边缘病变（平均[SD]年龄，47[11]岁），42 名（20%）有 4 个或更多边缘病变（平均[SD]年龄，44[11]岁）。有 4 个边缘病变或更多的个体更早达到运动和认知残疾。有边缘病变的患者的脑、白质和基底节的体积标准化值较低。而无边缘病变随时间缩小（每年-3.6%），边缘病变的体积稳定或增大（每年 2.2%；P<.001）。边缘病变的 T1 时间较长，提示组织破坏程度更严重，而无边缘病变则较短。在组织病理学分析中，所有在活体中扩展的 10 个边缘病变均有慢性活动性炎症。
慢性活动性病变很常见，与更具侵袭性的疾病有关，会持续造成组织损伤，即使在接受有效疾病修饰治疗的个体中也会发生。这些结果促使我们计划进行基于 MRI 的临床试验，以治疗 MS 中的边缘慢性炎症。
