Bjartmar Carl, Trapp Bruce D
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Neurotox Res. 2003;5(1-2):157-64. doi: 10.1007/BF03033380.
Accumulating data support axonal degeneration as the major determinant of irreversible neurological disability in patients with multiple sclerosis (MS). The extent of axonal injury correlates with the degree of inflammation in active MS lesions and occurs at early stages of disease, indicating that inflammatory demyelination is an important factor behind axon pathology at the relapsing-remitting stage of MS. Axonal loss from disease onset can remain clinically silent for many years, and permanent neurological disability develops when a threshold of axonal loss is reached and the CNS compensatory resources are exhausted. Lack of myelin-derived trophic support due to long term demyelination may cause continuous axonal degeneration in chronic inactive lesions at the secondary-progressive stage of MS. Axonal pathology is not limited to demyelinated lesions, but also extends into normal appearing white matter. The concept of MS as a neurodegenerative disorder has important clinical implications: First, proactive anti-inflammatory and immunomodulatory treatment should prevent or delay chronic disability since inflammation influences axonal injury. Second, the pathophysiological mechanisms underlying axonal degeneration in MS need to be clarified in order to develop novel neuroprotective therapeutics. Finally, surrogate markers of axonal pathology, such as N-acetyl aspartate, can be used to monitor axonal dysfunction, axonal loss and treatment efficiency in patients with MS.
越来越多的数据支持轴突退变是多发性硬化症（MS）患者不可逆神经功能障碍的主要决定因素。轴突损伤的程度与活动性MS病灶中的炎症程度相关，且发生在疾病的早期阶段，这表明炎症性脱髓鞘是MS复发缓解期轴突病变背后的一个重要因素。从疾病发作开始的轴突损失在临床上可能多年无症状，当轴突损失达到阈值且中枢神经系统的代偿资源耗尽时，就会出现永久性神经功能障碍。由于长期脱髓鞘导致的髓鞘源性营养支持缺乏，可能会在MS继发进展期的慢性非活动性病灶中引起持续的轴突退变。轴突病变不仅限于脱髓鞘病灶，还会延伸至外观正常的白质。将MS视为一种神经退行性疾病的概念具有重要的临床意义：第一，积极的抗炎和免疫调节治疗应预防或延缓慢性残疾，因为炎症会影响轴突损伤。第二，需要阐明MS中轴突退变的病理生理机制，以便开发新的神经保护疗法。最后，轴突病变的替代标志物，如N-乙酰天门冬氨酸，可用于监测MS患者的轴突功能障碍、轴突损失和治疗效果。
