Trapp B D, Ransohoff R, Rudick R
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Curr Opin Neurol. 1999 Jun;12(3):295-302. doi: 10.1097/00019052-199906000-00008.
In this review, data is summarized supporting the hypothesis that axonal loss is a major pathologic process responsible for irreversible neurologic disability in patients with multiple sclerosis. Pathologic studies implicate inflammatory demyelination as a principal cause of axonal transection and subsequent axonal degeneration. Axonal degeneration caused by chronic demyelination in the absence of active inflammation may also contribute to progressive disability in the later stages of the disease. Studies using magnetic resonance spectroscopy suggest that axonal loss begins at the onset of the disease, and studies using magnetic resonance imaging have documented brain atrophy in the earliest stages of multiple sclerosis. Brain atrophy increases during the relapsing-remitting disease stage without concurrent disability progression. This suggests that compensatory mechanisms maintain neurologic function, despite progressive brain tissue loss during the early stages of the disease. Beyond a threshold, however, further axonal loss leads to continuously progressive neurologic disability. We hypothesize that the rate and extent of axonal loss during relapsing-remitting multiple sclerosis determines when a patient enters the secondary progressive stage of the disease. This view of disease pathogenesis has several important implications. First, surrogate markers of axonal loss are needed to monitor the disease process for patient care and for clinical trials. We propose brain parenchymal fraction, a precise measure of whole-brain atrophy, as an attractive candidate for this purpose. Second, disease-modifying therapy should be used early in multiple sclerosis patients, before extensive axonal loss has occurred. Third, neuroprotective drugs should be tested in combination with anti-inflammatory drugs in multiple sclerosis patients. Finally, studies of the time course of axonal loss, and its mechanisms are critical for effective therapeutic intervention.
在本综述中，总结了相关数据，支持轴突损失是导致多发性硬化症患者不可逆神经功能残疾的主要病理过程这一假说。病理研究表明，炎性脱髓鞘是轴突横断及随后轴突退变的主要原因。在无活动性炎症情况下，由慢性脱髓鞘引起的轴突退变也可能导致疾病后期的进行性残疾。使用磁共振波谱的研究表明，轴突损失在疾病发作时就已开始，而使用磁共振成像的研究已记录到多发性硬化症最早阶段的脑萎缩。在复发缓解型疾病阶段，脑萎缩会增加，但残疾程度并无同步进展。这表明，尽管在疾病早期脑组织不断损失，但代偿机制维持了神经功能。然而，超过某个阈值后，进一步的轴突损失会导致神经功能残疾持续进展。我们推测，复发缓解型多发性硬化症期间轴突损失的速率和程度决定了患者何时进入疾病的继发进展阶段。这种疾病发病机制的观点具有几个重要意义。首先，需要轴突损失的替代标志物来监测疾病进程，以用于患者护理和临床试验。我们提出脑实质分数，一种精确测量全脑萎缩的指标，作为实现这一目的的一个有吸引力的候选指标。其次，疾病修饰疗法应在多发性硬化症患者早期使用，即在广泛的轴突损失发生之前。第三，应在多发性硬化症患者中测试神经保护药物与抗炎药物联合使用的效果。最后，对轴突损失的时间进程及其机制的研究对于有效的治疗干预至关重要。
