专家讲堂 | 董钊教授：免疫治疗——偏头痛治疗新方向（上）

偏头痛是一种反复发作、单侧为主的中重度搏动样头痛，常持续4~72 h，体力活动后加重，常见的伴随症状包括恶心、呕吐、畏光和畏声。全球约有10亿患者，其中女性居多。根据《Global Burden of Disease Study 2016》的数据显示，偏头痛是导致失能的第二大原因，其导致的失能患者数量超过其他所有神经系统疾病导致的失能患者数量总和。我国偏头痛流行病学调查显示：原发性头痛患病率高达23.8%，其中偏头痛患病率为9.3%，紧张型头痛为10.8%。头痛的分类

图1  I CHD-3将头痛分三大部分14类继发性头痛的危险信号1.全身症状，包括发烧；2.肿瘤病史；3.神经功能缺损（包括意识障碍）；4.突发性或者突发性发作；5.年龄较大（65岁以后发病）；6.头痛表现改变或最近出现新的头痛；7.体位性头痛；8.打喷嚏、咳嗽或者运动引起的痛觉；9.视神经乳头水肿；10.进行性头痛和不典型表现；11.怀孕或产褥期；12.伴有自主神经症状的眼痛；13.外伤后头痛；14.免疫系统病理状态，如HIV；15.头痛发作时过度使用止痛药或新药。偏头痛临床特点偏头痛发作的临床过程不仅仅是头痛，除头痛的表现外还有非头痛的症状。偏头痛的发作是一个连续的过程，头痛之前会出现前驱期和先兆期，之后会出现恢复期。偏头痛前驱期发生在头痛期出现的前1~2 d，患者出现非头痛症状，例如反复哈欠、多尿、颈部发硬、疲乏、情绪改变、光敏感和声音敏感。先兆期目前有六大症状：视觉先兆、感觉先兆、语言先兆、运动（偏瘫）先兆、脑干先兆和视网膜先兆。头痛发生前有先兆和非痛性事件，非痛性事件可分为前驱症状和诱发因素。日常诱发因素不能稳定诱发出偏头痛，大部分诱发因素没有存在的客观证明，部分诱发因素与前驱症状之间关系密切，比如光敏和光诱发，嗅觉敏感和味道诱发等。2014年—2019年12月在解放军总医院头痛中心和其他9个临床神经中心研究入组了4821名偏头痛就诊的患者，女性3762名，男性1059名。其中有先兆偏头痛714名，无先兆偏头痛4107名。儿童偏头痛105名。21.5%的偏头痛患者有前驱症状的体验（无先兆20.1%，有先兆30.0%）。偏头痛发病机制关于偏头痛的发病机制目前认为与遗传、离子通道、神经递质和脑环路相关。偏头痛遗传学特点偏头痛家族史常见，遗传率约42%。一项全基因组关联荟萃分析发现偏头痛有38个易感基因位点，而偏头痛的风险变异在血管和内脏平滑肌相关基因中富集。这些发现引人关注，因为关于偏头痛发病机制是否涉及血管，已争论多年。另一项分析的结果也提示遗传标志物在神经元中富集。总之，遗传学研究表明，除少数与偏头痛相关的单基因综合征（如家族性偏瘫型偏头痛）之外，偏头痛的风险由多基因决定。表1 家族性偏瘫型偏头痛——染色体显性遗传类型编号致病基因编码蛋白组织特异性首次报告年份FHM 1型19p13CACNA1AP/Q型Cav2.1-α1A亚基CNS突触前膜兴奋性神经元1996CellFHM 2型1q23ATP1A2Na+-K+ATP酶-α2亚基星形胶质细胞2003NatureGeneticsFHM 3型2q24SCN1ANav1.1-α1亚基CNS GABA能抑制性神经元2005Lancet在偏头痛发作时有很多脑区发生改变，下丘脑是偏头痛发作的起源，与脑干上、下端的特定区域相互作用。偏头痛先兆症状与皮层播散去极化（CSD）和皮层神经元的去极化/复极化有关。CSD是一种传播速度为2~6 mm/min的皮层去极化波，皮层去极化后很快发生复极化，伴发持久脑血流降低。CSD的去极化/复极化波动造成细胞外离子成分、pH和神经递质浓度大幅度转换。

图2 A、B：皮层扩步性抑制引起皮层去极化（红色）；C：去极化后很快发生复极化（蓝色）

图3 偏头痛的头痛与整个三叉神经的血管反射激活相关，在偏头痛头痛发作的时候，三叉神经血管反射系统发生激活偏头痛发作时，与疼痛相关的脑区发生改变，这些区域的改变正是治疗偏头痛的新靶点，不管是外周还是中枢。除了疼痛和疼痛相关的区域外，偏头痛发作与情绪调控和疼痛传导也存在一定关系。

图4 与疼痛相关的脑区偏头痛分类

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