Kremenchutzky M, Rice G P A, Baskerville J, Wingerchuk D M, Ebers G C
Department of Clinical Neurological Sciences, University of Western Ontario London, Ontario, Canada.
Brain. 2006 Mar;129(Pt 3):584-94. doi: 10.1093/brain/awh721. Epub 2006 Jan 9.
The clinical features of relapses and progression largely define multiple sclerosis phenotypes. A relapsing course is followed by chronic progression in some 80% of cases within 2 decades. The relationship between these phases and long-term outcome remains uncertain. We have analysed these clinical features within a well-studied natural history cohort with mean follow-up of 25 years. For the entire cohort, median times to reach Disability Status Scale (DSS) 6, 8 and 10 were 12.7, 20.6 and 43.9 years, respectively. Among 824 attack-onset patients, the great majority entered a progressive phase with a mean time to progression of 10.4 years. The effects of relapses often cloud the clinical onset of progression. However, there are circumstances where onset of progression is early, relatively discrete and identifiable at DSS of 2 or less. Three subgroups allow for clarity of outcome comparison and they are (i) cases of primary progressive (PP) disease, (ii) attack-onset disease where only a single attack has occurred before onset of progression (SAP) and (iii) secondary progressive (SP) disease where recovery from relapses allows recognition of the earliest clinical stages when progression begins. Here we compare survival curves in these three groups. Among cohorts of SAP (n = 140), PP (n = 219) and SP (n = 146) where progression was stratified by DSS at its onset, there was no difference in time to DSS 6, 8 and 10. These findings demonstrate that the progressive course is independent of relapses either preceding the onset of relapse-free progression or subsequent to it. Among SAP patients, the degree of recovery from the single defining exacerbation had no significant effect on outcome. The site of the original attack was not usually where progression began. The relatively stereotyped nature of the progressive phase seen in all progressive phenotypes suggests regional and/or functional differential susceptibility to a process that appears degenerative in nature. The highly prevalent distal corticospinal tract dysfunction in progressive disease and the pathologically demonstrated selective axonal loss seen in this tract raises the possibility of a dying back central axonopathy, at least in part independent of plaque location or burden. Despite considerable individual variation, the progressive course of disability seen in groups of PP, SAP and SP-DSS2 is similarly stereotyped in quality and pace and may entail mechanisms common to all forms of progressive multiple sclerosis. The possibility that this is the primary process in some cases must be considered.
复发和疾病进展的临床特征在很大程度上决定了多发性硬化的表型。在20年内，约80%的病例在复发病程后会进入慢性进展期。这些阶段与长期预后之间的关系仍不明确。我们在一个经过充分研究的自然史队列中分析了这些临床特征，该队列的平均随访时间为25年。对于整个队列，达到残疾状态量表（DSS）6级、8级和10级的中位时间分别为12.7年、20.6年和43.9年。在824例发作起病的患者中，绝大多数进入了进展期，平均进展时间为10.4年。复发的影响常常掩盖了疾病进展的临床起始。然而，在某些情况下，进展的起始较早、相对离散且在DSS为2或更低时即可识别。三个亚组有助于清晰地比较预后，它们分别是：（i）原发进展型（PP）疾病病例；（ii）进展前仅发生过一次发作的发作起病型疾病（SAP）；（iii）继发进展型（SP）疾病，复发后的恢复使得能够识别进展开始时的最早临床阶段。在此，我们比较这三组的生存曲线。在SAP（n = 140）、PP（n = 219）和SP（n = 146）队列中，根据进展起始时的DSS进行分层，达到DSS 6级、8级和10级的时间没有差异。这些发现表明，进展病程与无复发进展起始之前或之后的复发无关。在SAP患者中，单次明确发作的恢复程度对预后没有显著影响。最初发作的部位通常不是进展开始的部位。在所有进展型表型中所见的进展期相对固定的性质表明，对于一个本质上似乎是退行性的过程，存在区域和/或功能上的易感性差异。进展性疾病中高度普遍的远端皮质脊髓束功能障碍以及该束中病理显示的选择性轴突丢失增加了中枢轴突逆行性病变的可能性，至少部分独立于斑块的位置或负荷。尽管存在相当大的个体差异，但PP、SAP和SP-DSS²组中所见的残疾进展过程在性质和速度上同样固定，可能涉及所有形式的进展性多发性硬化的共同机制。在某些情况下，必须考虑这可能是主要过程的可能性。
