What preventive treatment options are there for migraine?
偏头痛is not curable, but preventive treatments are usually used to decrease the intensity and frequency of headache attacks in patients with frequent or chronic migraine. Usually, oral preventives such as topiramate, an anti-convulsive medication, and b-blockers are considered as first line treatments. Injectable treatments such as botulinum toxin (botox) and even greater occipital nerve block show good efficacy if first line treatments fail. Valproate and its derivatives, such as divalproex sodium, is an antiepileptic treatment also approved by the FDA and indicated in some European countries for the preventive treatment of migraine. We are now entering a new exciting era for the treatment of migraine with new migraine preventive treatments becoming available for our patients. The monoclonal antibodies against the calcitonin gene-related peptide, a small protein believed to be involved in migraine, offer new hopes to both patients and their clinicians. Non-pharmacological approaches may be preferred by some patients. Non-invasive neuromodulation techniques, for example, such as single pulse transcranial magnetic stimulation and vagus nerve stimulation have gained considerable ground in the treatment pathway of patients, particularly for those who fail or do not tolerate oral preventives and injectable treatments.
偏头痛的预防性治疗目前面临哪些挑战？
为每个患者选择正确的治疗可能是一项艰巨的任务，因为人们必须考虑疗效，副作用，治疗依从性以及经常成本和报销。
为每个患者选择正确的治疗可能是一项艰巨的任务，因为人们必须考虑疗效，副作用，治疗依从性以及经常成本和报销。Treatment compliance, potentially due to side effects, is often a limitation for oral preventives. Different countries may have guidelines for the treatment pathway a patient needs to follow. When it comes to treating women during pregnancy and breastfeeding non-pharmacological treatments should be preferred.
What are the latest breakthroughs in the prophylaxis of migraine with valproate?
Valproate has been approved for the prophylactic treatment of migraine after clinical trials found it effective in reducing migraine frequency, severity and duration of attacks in almost 40% of the patients. A double-blind crossover trial comparing the effectiveness of topiramate to valproate demonstrated that both medications were efficacious in decreasing headache frequency, intensity, and duration. Newer clinical studies that mainly aimed to compare the effect of alternative treatments to valproate show that valproate can still be an effective preventive treatment in reducing migraine frequency. Valproate has never been a first line treatment but our clinical experience and published case series suggest a role for valproate in the treatment pathway of vestibular migraine, rare forms of migraine with aura, such as hemiplegic migraine and migraine with complex sensory motor aura, and in post-traumatic headache, particularly with migraine features. Valproate has been also used in cases of status migrainosus and, randomised control studies suggest a role for valproate in the treatment of medication overuse headache in migraine patients. However, one has to consider the side effect profile, which includes, nausea, tremor, hair fall, menstrual irregularity, polycystic ovary, and weight gain. In women at the childbearing age, and during pregnancy, the use of valproate has even greater considerations.
What is the mechanism of action of valproate in migraine?
在偏头痛中丙戊酸的作用机理上尚不清楚。我的研究的一部分表明，丙戊酸在通过与GABAEGIC系统的相互作用来降低三阶丘脑神经元的三角丘脑兴奋性方面的作用。尽管丙戊酸作用机理仍然存在许多方面，但其对丘脑内三叉神经伤害性传播的影响也已得到其他人的确认。它进一步证明可以抑制皮质扩散抑郁症，这是偏头痛的实验模型。已经提出了其他机制在其他疾病中的作用方式，例如干扰ERK信号通路以及肌醇和蛛网膜酸代谢。瓣膜处理也已知可以增强DNA结合蛋白，因此导致多个基因表达的改变，其中许多涉及转录调控，细胞存活，细胞骨架修饰和信号转导。尽管这些生物学作用可能与其抗惊厥作用机理有关，但它们也可能导致瓣膜物质引起的重大出生缺陷。
为什么提高对丙戊酸使用的认识很重要？
偏头痛是一种常见的神经系统疾病，影响女性更多，尤其是在其生殖年龄。在育龄的妇女和怀孕期间，鉴于其与神经管缺陷无关的关联，应禁止使用丙戊酸盐其他先天性畸形and cognitive problems of the unborn child.
偏头痛是一种常见的神经系统疾病，影响女性更多，尤其是在其生殖年龄。在育龄的妇女和怀孕期间，鉴于其与神经管缺陷无关的关联，应禁止使用丙戊酸盐其他先天性畸形and cognitive problems of the unborn child. Studies found a significant association between the prenatal use of valproate andlower intelligent scores， 也，缺乏沟通斯基尔ls以及母亲接受过丙戊酸治疗的孩子的记忆问题。此外，来自使用valproate的母亲的孩子有five times higher risk of developing an autism spectrum disorder. Beyond the mental development adverse effects, valproate use is also link with delayed physical development in children exposed to valproate in utero.
Why was the consensus article developed?
共识论文是欧洲药品局与欧洲头痛联合会之间的合作。在2018年对药物宣传和风险评估委员会的最新审查中，它是在加强风险最小化措施的最新措施和临床建议的更新，以在育龄妇女的妇女中对替代性丙戊酸的使用进行更新。2014年发表的第一份审查建议在女性儿童，生育潜力和孕妇的女性中限制使用丙戊酸盐，这是由于子宫中暴露于丙戊酸的儿童畸形和神经发育问题的风险。关于2014年首次发布的实施限制有效性的数据，表明，在规定行为发生了变化时，仍有改进的余地。例如，一项法国的研究表明，育龄妇女暴露于丙戊酸盐没有改变，而暴露于丙戊酸酯的女性双极患者中只有三分之一满足2014年建议中指出的标准。英国癫痫学会的一项调查还显示，服用丙戊酸的女性中有70％不知道有关怀孕期间服用丙戊酸的危险。尽管无法使用有关偏头痛使用丙戊酸的数据，但可以假设处方药的行为和与偏头痛患者的风险进行交流也可能是有问题的。
共识文章的目的是什么？
This consensus paper aimed to accumulate the PRAC updated guidelines that are relevant to the preventive treatment of migraine with valproate, and to list the required measures needed by both clinicians and patients for the implementation of the guidelines, in order to minimize exposure to valproate during pregnancy. The overall aim is to alleviate the neurodevelopmental risks of valproate, by minimising exposure.
What benefit should it bring to the headache specialists/neurologist/ patients, what benefit are you hoping for?
The consensus paper emphasizes the contraindicated use of valproate for the prophylaxis of migraine in pregnancy or in women of childbearing age who are not using effective methods of contraception. It includes educational support to treating clinicians with regards to adherence to the pregnancy prevention programme and annual checks and discussions between treating physician and patient to evaluate individual circumstances and ensure engagement with contraception and understanding of the risks by the patient. It also includes important educational material that the patients need to have access to with regards to the use of valproate at different stages of life.
Would you like to pick out a relevant examples to illustrate the benefit/importance?
我认为这是非常必要的理解tient needs and circumstances change in the course of life. While valproate use may not present any risk at one stage of life, it may do so at another. From the beginning of the treatment a risk acknowledgment leaflet or form should be made available to the patient. Pregnancy should be excluded and highly effective contraception should be arranged. However, it is also important to ensure frequent consultation for female patients of childbearing potential as they may consider to have a child, or even have an unplanned pregnancy. More importantly, as more migraine preventive treatments become available, a more effective and appropriate treatment may be considered for patients who use valproate. The risks to the children of women who are using valproate outweigh any treatment benefits for this use. Hence, correct communication and frequent consultation of female patients currently using valproate, will ensure that patients are given the correct treatment for their condition, minimizing the adverse effects.
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