Abstract：
The failure of relapses and white matter lesions to properly explain long-term disability and progression in multiple sclerosis is compounded by its artificial separation into relapsing remitting, secondary progressive, and primary progressive pigeonholes. The well-known epidemiological disconnection between relapses and long-term disability progression has been rediscovered as \"progression independent of relapse activity\", i.e. smouldering multiple sclerosis. This smouldering associated worsening proceeds despite early and prolonged use of disease modification therapies, even those that are highly effective at preventing relapses and new/enhancing white matter lesions on MRI. We recognise that smouldering associated worsening and relapse/lesion associated worsening coexist, to varying extents. The extent of cortical demyelination has been shown to correlate significantly with the severity of diffuse injury in normal appearing white matter (post mortem histopathologically (r = 0.55; P = 0.001), and in vivo with MRI (r = -0.6874; P = 0.0006)) and does so independently of white matter lesion burden. Axon loss in the normal appearing white matter explains disability in multiple sclerosis better than focal white matter lesions do. Smouldering associated worsening typically manifests as a length-dependent central axonopathy. We propose a unifying model for multiple sclerosis pathogenesis, wherein accumulation of cortical lesion burden predisposes associated normal appearing white matter to diffuse injury, whilst also intensifying damage within white matter lesions. Our novel two-hit hypothesis implicates cortical disease as a culprit for smouldering multiple sclerosis, abetted by active focal inflammation in the white matter (and vice versa). Substantiation of the two-hit hypothesis would advance the importance of specific therapeutic intervention for (and monitoring of) cortical/meningeal inflammation in people with multiple sclerosis.
摘要：
复发和白质病变未能正确解释多发性硬化症的长期残疾和进展，其人工分离为复发缓解，二级进步,和初级渐进的鸽子洞。众所周知，复发与长期残疾进展之间的流行病学联系已被重新发现为“独立于复发活动的进展”，即闷烧多发性硬化症。尽管早期和长期使用疾病修饰疗法，但这种阴燃相关的恶化仍在继续，即使是那些在预防复发和MRI上新的/增强白质病变方面非常有效的患者。我们认识到阴燃相关恶化和复发/病变相关恶化并存，在不同程度上。皮质脱髓鞘的程度已被证明与正常出现的白质弥漫性损伤的严重程度显著相关（死后组织病理学（r=0.55；P=0.001），和体内MRI（r=-0.6874；P=0.0006），并且与白质病变负荷无关。正常出现的白质中的轴突丢失比局灶性白质病变更好地解释了多发性硬化症的残疾。与阴燃相关的恶化通常表现为长度依赖性中枢轴突病。我们提出了多发性硬化症发病机制的统一模型，其中皮质病变负荷的积累使正常出现的白质与弥漫性损伤相关，同时也加剧了白质病变内的损伤。我们新颖的两次命中假设暗示皮质疾病是阴燃多发性硬化症的罪魁祸首，由白质的活动性局灶性炎症（反之亦然）。两次命中假设的证实将提高特定治疗干预对多发性硬化症患者的皮质/脑膜炎症(和监测)的重要性。
