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偏头痛的原因和治疗方法
偏头痛并不是简单的“头痛医头”，它是一种复杂的大脑神经和血管疾病，其根本原因在于遗传基因与环境因素的相互作用，而目前的治疗方法涵盖了从补充特定营养素、使用传统稳定神经的药物，到针对特定蛋白质的新型靶向药物以及激素调节等多种手段。
下面我们将用通俗易懂的语言，详细为您拆解偏头痛的“前世今生”以及应对策略。
一、 偏头痛到底是怎么引起的？
偏头痛的发生，就像是脑子里经历了一场错综复杂的“风暴”，具体原因可以归结为以下几个方面：
1. 基因里自带的“易感性”（遗传因素） 偏头痛在很大程度上是“天生”的。科学家们通过大规模的研究发现，目前已知有超过180种基因变异（可以理解为人体生命图谱中的微小拼写错误）会让人更容易患上偏头痛。虽然每一个微小的基因变异只会让偏头痛的风险增加一点点，但它们叠加在一起，就会让大脑的神经或血管处于一种容易“走火”的状态。 在一些罕见的偏头痛类型中（比如“家族性偏瘫型偏头痛”，这类患者在头痛发作时会出现身体一侧无力的症状），科学家找到了更明确的“罪魁祸首”。比如名为 CACNA1A、ATP1A2 和 SCN1A 的基因发生了突变。这些基因原本负责制造大脑细胞上的“门控通道”（比如钙离子通道、钠钾泵等），用来控制钾离子、钠离子等化学物质的进出。一旦这些门坏了，神经突触（神经元之间传递信号的缝隙）里的神经递质和钾离子就会异常增多，导致大脑异常兴奋。
2. 大脑里的“海啸”：皮层扩布性抑制（CSD） 这是偏头痛发作时大脑里真实发生的物理和化学变化。你可以把大脑想象成一片平静的湖面，“皮层扩布性抑制”就像是有人在湖中心扔了一块石头，激起了一波向外扩散的涟漪，或者说像是一场缓慢席卷大脑皮层（大脑最外层）的“停电”或“风暴”。 在这场风暴中，大量的钾离子和谷氨酸（一种让神经兴奋的化学物质）从细胞里跑了出来，导致神经元（大脑细胞）发生剧烈的电位变化。这种大脑皮层的异常波动，不仅会引发头痛，也是导致偏头痛“先兆”的直接原因。 所谓“先兆”，就是有些人在头痛发作前，眼前会看到闪光、水波纹、盲点，或者手脚发麻、说话不利索。研究发现，有一种特殊情况叫做“无头痛的典型先兆”（也叫隐性偏头痛），也就是患者只出现这些视觉或感觉上的异常“风暴”，但随后并没有头痛发作。这种只发先兆不头痛的情况，在所有偏头痛患者中约占4%，而在有先兆偏头痛的患者中，大约38%的人在人生的某个阶段会经历这种现象。
3. 关键的“疼痛信使”：CGRP等神经肽 在偏头痛发作时，人体内一种叫做“降钙素基因相关肽（英文简称CGRP）”的蛋白质起到了推波助澜的作用。你可以把它理解为一种“疼痛信号放大器”。当大脑神经受到刺激时，会释放出CGRP，它不仅会让脑部的血管扩张，还会引发局部的炎症反应，把强烈的疼痛信号传递给大脑，让人感到头痛欲裂。
4. 激素的剧烈波动（尤其是女性的雌激素） 偏头痛在女性中更为常见，这与雌激素的波动密切相关。很多女性会发现，偏头痛往往在月经来潮前发作，这是因为此时体内的雌激素水平会出现急剧下降，这种“断崖式”的下跌触发了偏头痛。此外，在女性进入围绝经期（即更年期前后）时，体内激素水平极不稳定，这种动荡不仅会导致潮热、情绪波动，还会让偏头痛的发病率明显上升。
5. 营养物质的缺乏：镁离子 镁是人体内一种非常重要的矿物质，它就像是大脑神经的“镇定剂”。许多研究人员指出，体内镁元素的缺乏，可能会导致大脑容易触发上述的“皮层扩布性抑制（大脑风暴）”，或者导致谷氨酸（兴奋物质）传递异常。因此，镁缺乏被认为是偏头痛发病机制中一个不容忽视的环节。
6. 偏头痛的“难兄难弟”：抑郁与脑卒中 偏头痛往往不是孤立存在的，它和一些其他疾病共享着生物学基础。
- 抑郁症：偏头痛患者患抑郁症的风险是常人的2.5倍，如果是慢性偏头痛或有先兆的偏头痛，这个风险还会更高。这不仅因为长期的疼痛折磨人，更因为它们在大脑里有着共同的“病根”，比如5-羟色胺（一种调节情绪和疼痛的物质）系统的异常，以及免疫系统和激素的异常。
- 脑卒中（中风）：偏头痛（尤其是伴有先兆的偏头痛）是脑卒中的一个独立危险因素。在大脑中，偏头痛引起的血管异常收缩、内皮细胞（血管内壁的一层薄膜）功能障碍以及局部炎症，都可能增加中风的风险。有一种极其罕见且危险的并发症叫做“偏头痛性脑梗死”，它的年发病率大约为十万分之0.80，女性发病率几乎是男性的两倍（患者平均年龄通常在29到39岁之间）。这类患者在偏头痛发作时，先兆症状持续时间超过60分钟，并且脑部影像学检查会发现相关的脑血管出现了梗死（即血管堵死导致脑组织坏死）。
二、 偏头痛应该怎么治疗和预防？
因为偏头痛的成因复杂，目前并没有一种可以“一劳永逸”去根的特效药，但我们有非常多有效的手段来减少它的发作频率、减轻发作时的痛苦。目前的治疗方法主要分为以下几大类：
1. 新兴的“精准打击”：CGRP拮抗剂 既然我们知道CGRP（降钙素基因相关肽）是传递偏头痛信号的“核心信使”，科学家们就发明了专门针对它的药物——CGRP拮抗剂。这类药物就像是给CGRP这个信使戴上了手铐，或者堵住了接收信使的“门”，从而阻断疼痛信号的传递。这是一种非常新颖且高效的预防性治疗方法，正越来越广泛地应用于临床。
2. 跨界帮忙的“老药”：抗癫痫药与降压药 有些患者可能会疑惑，为什么医生会给我开治疗癫痫或高血压的药来治头痛？其实，偏头痛和癫痫在很多发病机制上是相通的，它们都涉及到大脑神经元通道的异常和大脑异常放电。因此，一些抗癫痫药物（如拉莫三嗪、丙戊酸钠或托吡酯）可以起到稳定神经细胞、提高大脑对异常刺激耐受力的作用，被广泛用于预防偏头痛发作。 同样，一些钙离子通道阻滞剂（原本多用于降血压，如氟桂利嗪、维拉帕米），因为能调节细胞上的钙离子通道，也被用来治疗复杂的偏头痛（如偏瘫型偏头痛）。
3. 补充“脑部镇定剂”：镁剂治疗 既然镁元素的缺乏与偏头痛有关，那么补充镁就成了一个顺理成章的治疗选择。许多临床医生认为，在日常饮食或通过药物补充合适剂量和形式的镁，可以作为预防偏头痛发作的手段。这对于那些对传统西药有禁忌症，或者更倾向于温和疗法的患者来说是个好消息。而且研究指出，在偏头痛发作期间，静脉注射高剂量的镁，可能也是一种有效的缓解方法。
4. 激素调节治疗（针对女性患者） 对于因为月经或围绝经期雌激素剧烈波动引起的偏头痛，可以通过医疗手段稳定体内的激素水平。例如，使用激素替代疗法（HRT）可以帮助一些围绝经期女性改善偏头痛症状。对于纯粹的月经期偏头痛（即只在月经前后发作），可以在月经前后这段特殊时期，提前进行预防性治疗。 不过需要特别警惕的是：含有雌激素的药物可能会增加血栓和脑卒中的风险。如果患者本身患有伴有先兆的偏头痛，患中风的风险本来就偏高，这种情况下使用激素治疗必须非常谨慎，通常只有在其他治疗都无效时才考虑。
5. 寻找未来的“神药”：新的基因靶点 科学家们从未停止寻找更好药物的脚步。近期，通过对数十万人（包括芬兰数据库的4万多名偏头痛患者和36万多名健康人，以及英国生物样本库的数据）的大数据和基因分析，科学家发现了一个名为 GSTM4 的基因，它是一个非常有潜力的偏头痛治疗新靶点。研究数据显示，从遗传学角度预测，GSTM4的作用与偏头痛发病率降低密切相关（总体偏头痛风险降低，OR值约为0.91；有先兆和无先兆偏头痛风险降低，OR值约为0.90），这意味着未来如果能研发出针对这个基因或其产生蛋白质的药物，可能会给偏头痛患者带来全新的希望。
6. 发作时的紧急用药与禁忌 在偏头痛突然发作时，普通的止痛药或者专门的曲普坦类药物（Triptans）以及麦角胺类药物可以用来快速止痛。然而，有极少数患者需要特别注意：如果患者被诊断为前文提到的“偏头痛性脑梗死”（即偏头痛引起了中风），那么绝对不能使用曲普坦类和麦角胺类药物。因为这两类药物的作用机制是让血管收缩（以缓解头痛），但在大脑已经缺血梗死的情况下，让血管收缩只会雪上加霜。这类特殊的患者需要使用的是抗血小板药物（防止血液凝固）以及偏头痛预防性药物，以避免未来再次发生危险事件。
总结建议 如果您或您的家人经常受到偏头痛的困扰，千万不要仅仅依赖硬扛或者乱吃止痛药。偏头痛是一种有着明确生理基础的神经系统疾病。从青少年的患病数据来看，8岁到18岁的孩子中，有11%的人患有偏头痛（其中8%是无先兆偏头痛，3%是有先兆偏头痛），说明这种疾病影响的人群极其广泛。正确的做法是记录头痛发作的规律（是否与月经相关、是否有闪光等先兆），在医生的指导下，选择适合自己的预防药物（如稳定神经的药物或新型的CGRP拮抗剂）、注意补充营养（如镁元素），并严格控制高血压、吸烟等可能增加中风风险的不良因素。
References
1Genetics of migraine: where are we now?PubMed
Lou Grangeon, Kristin Sophie Lange, Marta Waliszewska-Prosół, et al.
J Headache Pain. 2023 Feb 20;24(1):12. doi: 10.1186/s10194-023-01547-8.
Migraine is a complex brain disorder explained by the interaction of genetic and environmental factors. In monogenic migraines, including familial hemiplegic migraine and migraine with aura associated with hereditary small-vessel disorders, the identified genes code for proteins expressed in neurons, glial cells, or vessels, all of which increase susceptibility to cortical spreading depression. The study of monogenic migraines has shown that the neurovascular unit plays a prominent role in migraine. Genome-wide association studies have identified numerous susceptibility variants that each result in only a small increase in overall migraine risk. The more than 180 known variants belong to several complex networks of "pro-migraine" molecular abnormalities, which are mainly neuronal or vascular. Genetics has also highlighted the importance of shared genetic factors between migraine and its major co-morbidities, including depression and high blood pressure. Further studies are still needed to map all of the susceptibility loci for migraine and then to understand how these genomic variants lead to migraine cell phenotypes.
2Multi-omics Mendelian randomization integrating GWAS, eQTL and pQTL data revealed GSTM4 as a potential drug target for migraine.PubMed
Xinyue Sun, Bohong Chen, Yi Qi, et al.
J Headache Pain. 2024 Jul 22;25(1):117. doi: 10.1186/s10194-024-01828-w.
INTRODUCTION: Migraine, as a complex neurological disease, brings heavy burden to patients and society. Despite the availability of established therapies, existing medications have limited efficacy. Thus, we aimed to find the drug targets that improve the prognosis of migraine. METHOD: We used Mendelian Randomization (MR) and Summary-data-based MR (SMR) analyses to study possible drug targets of migraine by summary statistics from FinnGen cohorts (nCase = 44,616, nControl = 367,565), with further replication in UK Biobank (nCase = 26,052, nControl = 487,214). Genetic instruments were obtained from eQTLGen and UKB-PPP to verify the drug targets at the gene expression and protein levels. The additional analyses including Bayesian co-localization, the heterogeneity in dependent instruments(HEIDI), Linkage Disequilibrium Score(LDSC), bidirectional MR, multivariate MR(MVMR), heterogeneity test, horizontal pleiotropy test, and Steiger filtering were implemented to consolidate the findings further. Lastly, drug prediction analysis and phenome-wide association study(PheWAS) were employed to imply the possibility of drug targets for future clinical applications. RESULT: The MR analysis of eQTL data showed that four drug targets (PROCR, GSTM4, SLC4A1, and TNFRSF10A) were significantly associated with migraine risk in both the FinnGen and UK Biobank cohorts. However, only GSTM4 exhibited consistent effect directions across the two outcomes(Discovery cohort: OR(95%CI) = 0.94(0.93-0.96); p = 2.70e - 10; Replication cohort: OR(95%CI) = 0.93(0.91-0.94); p = 4.21e - 17). Furthermore, GSTM4 passed the SMR at p < 0.05 and HEIDI test at p > 0.05 at both the gene expression and protein levels. The protein-level MR analysis revealed a strong correlation between genetically predicted GSTM4 with a lower incidence of migraine and its subtypes(Overall migraine: OR(95%CI) = 0.91(0.87-0.95); p = 6.98e-05; Migraine with aura(MA): OR(95%CI) = 0.90(0.85-0.96); p = 2.54e-03; Migraine without aura(MO): OR(95%CI) = 0.90(0.83-0.96); p = 2.87e-03), indicating a strong co-localization relationship (PPH4 = 0.86). Further analyses provided additional validation for the possibility of GSTM4 as a migraine treatment target. CONCLUSION: This study identifies GSTM4 as a potential druggable gene and promising therapeutic target for migraine.
3Migraine Aura Without Headache [corrected].PubMed
Divya R Shah, Sonam Dilwali, Deborah I Friedman
Curr Pain Headache Rep. 2018 Sep 17;22(11):77. doi: 10.1007/s11916-018-0725-1.
PURPOSE OF REVIEW: This review evaluates and explains our current understanding of a rare subtype of migraine, typical aura without headache, also known as migraine aura without headache or acephalgic migraine. RECENT FINDINGS: Typical aura without headache is a known entity within the spectrum of migraine. Its pathophysiology is suggested to be similar to classic migraines, with cortical spreading depression leading to aura formation but without an associated headache. No clinical trials have been performed to evaluate treatment options, but case reports suggest that most patients will respond to the traditional treatments for migraine with aura. Bilateral greater occipital nerve blocks may be helpful in aborting migraine with prolonged aura. Transcranial magnetic stimulation has shown efficacy in aborting attacks of migraine with aura but has not been specifically tested in isolated aura. Typical aura without headache occurs exclusively in 4% patients with migraine, and may take place at some point in 38% of patients with migraine with aura. Typical aura without headache commonly presents with visual aura without headache, brainstem aura without headache, and can also develop later in life, known as late-onset migraine accompaniment.
4Hemiplegic Migraine.PubMed
Arathi Nandyala, Tulsi Shah, Jessica Ailani
Curr Neurol Neurosci Rep. 2023 Jul;23(7):381-387. doi: 10.1007/s11910-023-01277-z. Epub 2023 May 29.
PURPOSE OF REVIEW: In this article, we review recent updates to the epidemiology, diagnostic testing, genetics, pathophysiology, and management of hemiplegic migraine. RECENT FINDINGS: While three genes have been historically associated with hemiplegic migraine, recent studies suggest two additional genes may also be implicated including PPRT2 and SLC1A3. Hemiplegic migraine is a severe subset of migraine with aura with symptoms including reversible hemiparesis in addition to other aura symptoms such as visual, sensory, or speech. The exact pathophysiology of hemiplegic migraine is not clear, but it is thought that this phenomenon is due to neuronal and glial depolarization causing cortical spreading depression. Due to the severity of presentation as well as the numerous mimickers, it is important to know a comprehensive differential and work-up. Given the low prevalence of the disease, most studies regarding treatment are limited to case studies. There is still an important need for further and larger studies regarding management of these cases.
5Cadasil.PubMed
Hugues Chabriat, Anne Joutel, Martin Dichgans, et al.
Lancet Neurol. 2009 Jul;8(7):643-53. doi: 10.1016/S1474-4422(09)70127-9.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. Clinical and neuroimaging features resemble those of sporadic small-artery disease, although patients with CADASIL have an earlier age at onset of stroke events, an increased frequency of migraine with aura, and a slightly variable pattern of ischaemic white-matter lesions on brain MRI. NOTCH3 (Notch homolog 3), the gene involved in CADASIL, encodes a transmembrane receptor primarily expressed in systemic arterial smooth-muscle cells. Pathogenetic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, which accumulates in small arteries of affected individuals. Functional and imaging studies in cultured cells, genetically engineered mice, and patients with CADASIL have all provided insights into the molecular and vascular mechanisms underlying this disease. A recent multicentre trial in patients with cognitive impairment emphasises the feasibility of randomised trials in patients with CADASIL. In this Review, we summarise the current understanding of CADASIL, a devastating disorder that also serves as a model for the more common forms of subcortical ischaemic strokes and pure vascular dementia.
6Migraine Aura: Pathophysiology, Mimics, and Treatment Options.PubMed
Clare L Fraser, Jenny L Hepschke, Bronwyn Jenkins, et al.
Semin Neurol. 2019 Dec;39(6):739-748. doi: 10.1055/s-0039-1700525. Epub 2019 Dec 17.
Recent insights into the clinical presentation and pathophysiology of migraine aura have paved the way for new treatments for this common but frequently debilitating condition. Marked efflux of cellular potassium and glutamate contributes to the cortical spreading depression that forms the electrophysiological basis of migraine aura phenomena. Secondary vascular perturbations also contribute to the various symptoms of a migraine attack. Calcitonin gene-related peptide (CGRP) plays a key role in many of these steps, and a growing class of CGRP-antagonists have emerged as a novel, efficacious preventative therapy. It is still not fully understood why a preponderance of migraine aura symptoms is visual, and this issue is an active area of research. In addition, the pathophysiological changes responsible for visual snow syndrome are under investigation. Before diagnosing a patient with migraine aura, it is important to consider the differential diagnosis of transient visual phenomena, with attention to clinical features that may suggest conditions such as retinal disorders, transient ischemic attack, or occipital epilepsy.
7Hemiplegic migraine.PubMed
Irene de Boer, Jakob M Hansen, Gisela M Terwindt
Handb Clin Neurol. 2024;199:353-365. doi: 10.1016/B978-0-12-823357-3.00015-X.
Hemiplegic migraine (HM) is a rare subtype of migraine with aura in which the aura phase includes transient motor weakness. Diagnosis is based on the International Classification of Headache Disorders criteria (ICHD-3). The most important diagnostic tools remain a patient interview, neurological examination during attacks, and exclusion of other disorders, such as epilepsy, stroke, encephalitis and secondary headache syndromes. Hemiplegic migraine can occur either familial or sporadic. Three genes, CACNA1A, ATP1A2, and SCN1A have been identified. Taken together, mutations in these three genes predict increased neurotransmitter and potassium ion levels at the synaptic cleft, which facilitates cortical spreading depolarization, the phenomenon underlying the migraine aura. The presence of several symptoms, including extensive weakness and brainstem manifestations increase the likelihood of finding a monogenic cause. While the diagnosis can be confirmed by genetic testing, it cannot be excluded if one of the known (F)HM genes is not implicated. Most patients with hemiplegic migraine without a mutation in CACNA1A, ATP1A2, or SCN1A display a mild phenotype that is more akin to that of common (nonhemiplegic) migraine. Additional diagnostics such as brain imaging, cerebrospinal fluid analysis or an electroencephalography are mainly performed to exclude other causes of focal neurologic symptoms associated with hemiparesis and headache. Due to the rarity of the disorder, current treatment recommendations are based on small, unblinded studies and empirical data.
8Diagnostic and therapeutic aspects of hemiplegic migraine.PubMed
Vincenzo Di Stefano, Marianna Gabriella Rispoli, Noemi Pellegrino, et al.
J Neurol Neurosurg Psychiatry. 2020 Jul;91(7):764-771. doi: 10.1136/jnnp-2020-322850. Epub 2020 May 19.
Hemiplegic migraine (HM) is a clinically and genetically heterogeneous condition with attacks of headache and motor weakness which may be associated with impaired consciousness, cerebellar ataxia and intellectual disability. Motor symptoms usually last <72 hours and are associated with visual or sensory manifestations, speech impairment or brainstem aura. HM can occur as a sporadic HM or familiar HM with an autosomal dominant mode of inheritance. Mutations in CACNA1A, ATP1A2 and SCN1A encoding proteins involved in ion transport are implicated. The pathophysiology of HM is close to the process of typical migraine with aura, but appearing with a lower threshold and more severity. We reviewed epidemiology, clinical presentation, diagnostic assessment, differential diagnosis and treatment of HM to offer the best evidence of this rare condition. The differential diagnosis of HM is broad, including other types of migraine and any condition that can cause transitory neurological signs and symptoms. Neuroimaging, cerebrospinal fluid analysis and electroencephalography are useful, but the diagnosis is clinical with a genetic confirmation. The management relies on the control of triggering factors and even hospitalisation in case of long-lasting auras. As HM is a rare condition, there are no randomised controlled trials, but the evidence for the treatment comes from small studies.
9Understanding the Biological Relationship between Migraine and Depression.PubMed
Adrián Viudez-Martínez, Abraham B Torregrosa, Francisco Navarrete, et al.
Biomolecules. 2024 Jan 30;14(2):163. doi: 10.3390/biom14020163.
Migraine is a highly prevalent neurological disorder. Among the risk factors identified, psychiatric comorbidities, such as depression, seem to play an important role in its onset and clinical course. Patients with migraine are 2.5 times more likely to develop a depressive disorder; this risk becomes even higher in patients suffering from chronic migraine or migraine with aura. This relationship is bidirectional, since depression also predicts an earlier/worse onset of migraine, increasing the risk of migraine chronicity and, consequently, requiring a higher healthcare expenditure compared to migraine alone. All these data suggest that migraine and depression may share overlapping biological mechanisms. Herein, this review explores this topic in further detail: firstly, by introducing the common epidemiological and risk factors for this comorbidity; secondly, by focusing on providing the cumulative evidence of common biological aspects, with a particular emphasis on the serotoninergic system, neuropeptides such as calcitonin-gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), substance P, neuropeptide Y and orexins, sexual hormones, and the immune system; lastly, by remarking on the future challenges required to elucidate the etiopathological mechanisms of migraine and depression and providing updated information regarding new key targets for the pharmacological treatment of these clinical entities.
10Familial hemiplegic migraine.PubMed
Maria Dolores Villar-Martinez, David Moreno-Ajona, Peter J Goadsby
Handb Clin Neurol. 2024;203:135-144. doi: 10.1016/B978-0-323-90820-7.00007-0.
Hemiplegic migraine consists of attacks of migraine with aura that includes reversible motor weakness. It is classified as familial or sporadic depending on the involvement or not of a first or second degree relative. The most described subtypes of familial hemiplegic migraine include FHM1, FHM2, and FHM3. These have been demonstrated to have a mutation in either CACNA1A, ATP1A2 or SCN1A, which encode different subunits of channels, involving P/Q-type calcium channel, Na/K pump and Na channel, respectively, located in neurons and glial cells. Mutations localized in different genes are defined as "other loci." Patients with a known mutation can have different genetic penetrance, and may present a more complex and disabling phenotype that develops earlier in life. The clinical manifestations can be similar in the three mutations, including neurologic comorbidities other than muscular weakness, such as episodes of loss of consciousness, epilepsy, gait or limb ataxia or movement disorders, among others. Treatment includes antiepileptics such as lamotrigine, valproate or topiramate, calcium blockers such as flunarizine or verapamil and acetazolamide.
11Primary headache epidemiology in children and adolescents: a systematic review and meta-analysis.PubMed
Agnese Onofri, Umberto Pensato, Chiara Rosignoli, et al.
J Headache Pain. 2023 Feb 14;24(1):8. doi: 10.1186/s10194-023-01541-0.
INTRODUCTION: Headache is the most prevalent neurological manifestation in adults and one of the leading causes of disability worldwide. In children and adolescents, headaches are arguably responsible for a remarkable impact on physical and psychological issues, yet high-quality evidence is scarce. MATERIAL AND METHODS: We searched cross-sectional and cohort studies in Embase, Medline, Web of Science, and Cochrane databases from January 1988 to June 2022 to identify the prevalence of headaches in 8-18 years old individuals. The risk of bias was examined with the Joanna Briggs Institute (JBI) scale. A random-effects model was used to estimate the pooled prevalence of pediatric headache. Subgroup analyses based on headache subtypes were also conducted. RESULTS: Out of 5,486 papers retrieved electronically, we identified 48 studies that fulfilled our inclusion criteria. The pooled prevalence of primary headaches was 11% for migraine overall [95%CI: 9-14%], 8% for migraine without aura (MwoA) [95%CI: 5-12%], 3% for migraine with aura (MwA) [95%CI:2-4%] and 17% for tension-type headache (TTH) [95% CI: 12-23%]. The pooled prevalence of overall primary headache in children and adolescents was 62% [95% CI: 53-70%], with prevalence in females and males of 38% [95% CI: 16-66%] and 27% [95% CI: 11-53%] respectively. After the removal of studies ranked as low-quality according to the JBI scale, prevalence rates were not substantially different. Epidemiological data on less common primary headaches, such as trigeminal autonomic cephalalgias, were lacking. CONCLUSION: We found an overall remarkably high prevalence of primary headaches in children and adolescents, even if flawed by a high degree of heterogeneity. Further up-to-date studies are warranted to complete the picture of pediatric headache-related burden to enhance specific public interventions.
12Magnesium as an Important Factor in the Pathogenesis and Treatment of Migraine-From Theory to Practice.PubMed
Izabela Domitrz, Joanna Cegielska
Nutrients. 2022 Mar 5;14(5):1089. doi: 10.3390/nu14051089.
So far, no coherent and convincing theory has been developed to fully explain the pathogenesis of migraine, although many researchers and experts emphasize its association with spreading cortical depression, oxidative stress, vascular changes, nervous excitement, neurotransmitter release, and electrolyte disturbances. The contribution of magnesium deficiency to the induction of cortical depression or abnormal glutamatergic neurotransmission is a likely mechanism of the magnesium-migraine relationship. Hence, there is interest in various methods of assessing magnesium ion deficiency and attempts to study the relationship of its intra- and extracellular levels with the induction of migraine attacks. At the same time, many clinicians believe that magnesium supplementation in the right dose and form can be a treatment to prevent migraine attacks, especially in those patients who have identified contraindications to standard medications or their different preferences. However, there are no reliable publications confirming the role of magnesium deficiency in the diet as a factor causing migraine attacks. It also seems interesting to deepen the research on the administration of high doses of magnesium intravenously during migraine attacks. The aim of the study was to discuss the probable mechanisms of correlation of magnesium deficiency with migraine, as well as to present the current clinical proposals for the use of various magnesium preparations in complementary or substitute pharmacotherapy of migraine. The summary of the results of research and clinical observations to date gives hope of finding a trigger for migraine attacks (especially migraine with aura), which may turn out to be easy to diagnose and eliminate with pharmacological and dietary supplementation.
13Migraine and stroke: correlation, coexistence, dependence - a modern perspective.PubMed
Michał Borończyk, Anna Zduńska, Julia Węgrzynek-Gallina, et al.
J Headache Pain. 2025 Feb 20;26(1):39. doi: 10.1186/s10194-025-01973-w.
BACKGROUND: Migraine is a chronic neurological condition that has a well-documented, yet not fully understood connection to stroke, particularly in patients who experience migraine with aura (MA). Although migraine can rarely be directly related to stroke, in the form of migrainous infarction, it serves as an independent risk factor, particularly when combined with other factors such as smoking or hypertension. This study will thoroughly review and summarize the existing literature regarding the relationship between migraine and stroke. MAIN TEXT: Several key processes are common to both stroke and migraine. These include cortical spreading depression, particularly in MA, endothelial dysfunction, which activates local inflammatory responses, and vasculopathy, which often appears as white matter hyperintensities on neuroimaging. Furthermore, microRNAs also play a significant role in the pathogenesis of both migraine and stroke by targeting genes such as CALCA, which regulates calcitonin gene-related peptide, a factor involved in the pathophysiology of both conditions. There are also several genetic links between migraine and stroke, including both monogenic diseases and common risk loci. Moreover, various conditions are linked to both migraine and stroke, including patent foramen ovale (PFO), atrial fibrillation, carotid artery dissection, platelet dysfunction, dyslipidemia, obesity, hyperhomocysteinemia, and elevated estrogen levels, such as in combined hormonal contraceptives. Notably, PFO is often found in patients who have experienced a cryptogenic stroke, as well as in those with MA. While microemboli associated with PFO may provoke ischemic events and migraine attacks, the effectiveness of PFO closure in alleviating migraine symptoms has produced varying results. Migraine is linked to worse outcomes after ischemic stroke, including larger stroke volumes and poorer functional outcomes, while the connection between migraines and hemorrhagic stroke is less understood. Furthermore, migraine may serve as a stroke mimic (condition presenting with symptoms similar to ischemic stroke) or a stroke chameleon (unrecognized stroke misdiagnosed as migraine), leading to significant diagnostic and treatment errors. CONCLUSIONS: The interplay between migraine and stroke is complex, involving shared pathophysiology and overlapping risk factors. While migraine can serve as both a cause and a risk factor for stroke, the precise mechanisms remain unclear, warranting further research to clarify their connection and enhance clinical management.
14Migrainous infarction.PubMed
Chia-Chun Chiang, Shih-Pin Chen
Handb Clin Neurol. 2024;199:465-474. doi: 10.1016/B978-0-12-823357-3.00021-5.
Migrainous infarction is defined as a migraine attack occurring as migraine with aura, typical of the patient's previous attacks, except that one or more aura symptoms persist for >60min, and neuroimaging demonstrates ischemic infarct in the relevant area. To better understand migrainous infarction, one must disentangle the complex interactions between migraine and stroke. In this chapter, we first discuss the migraine-stroke association in sections including "Increased Risks of Stroke and Subclinical Infarcts in Patients With Migraine," "Migrainous Headache Cooccurring or Triggered by Ischemic Stroke," "Stroke Progression in Patients With Migraine," and "Clinic Conditions Associated With Higher Risks of Both Migraine and Stroke." As an extreme example of migraine-stroke association, the annual incidence of migrainous infarction was reported to be 0.80/100,000/year, with the incidence in females nearly twofold that of male patients. Patients diagnosed with migrainous infarction are typically younger (average age 29-39 in case series), have fewer traditional vascular risk factors, and have more favorable prognosis compared to strokes from traditional risk factors. Thorough evaluation is recommended to rule out other etiologies of stroke. Patients diagnosed with migrainous infarction should receive antiplatelet therapy and migraine preventive therapy to avoid future events. Vasoactive medications, including triptans and ergots, should be avoided.
15Migraine and perimenopause.PubMed
Khatera Ibrahimi, Emile G M Couturier, Antoinette MaassenVanDenBrink
Maturitas. 2014 Aug;78(4):277-80. doi: 10.1016/j.maturitas.2014.05.018. Epub 2014 Jun 2.
Perimenopause and migraine are closely linked. The hormonal instability during the perimenopausal period not only causes vasomotor symptoms and mood disturbances, but also increases migraine incidence. Women do report new onset migraine during this period, but the increased incidence is reported by women with menstrually related migraine (MRM). The hormonal fluctuations can be stabilized with hormone replacement therapy (HRT), while simultaneously improving the migraine in some patients. The increased stroke risk in women with migraine with aura (MA) should be taken into consideration when intending to treat perimenopausal women with migraine with HRT.
16Migraine and stroke.PubMed
Yonghua Zhang, Aasheeta Parikh, Shuo Qian
Stroke Vasc Neurol. 2017 May 29;2(3):160-167. doi: 10.1136/svn-2017-000077. eCollection 2017 Sep.
Migraines are generally considered a relatively benign neurological condition. However, research has shown an association between migraines and stroke, and especially between migraine with aura and ischaemic stroke. Patients can also suffer from migrainous infarction, a subset of ischaemic stroke that often occurs in the posterior circulation of younger women. The exact pathogenesis of migrainous infarct is not known, but it is theorised that the duration and local neuronal energy level from cortical spreading depression may be a key factor. Other factors contributing to migrainous infarct may include vascular, inflammatory, endothelial structure, patent foramen ovale, gender, oral contraceptive pill use and smoking. Vasoconstrictors such as the triptan and ergot class are commonly used to treat migraines and may also play a role. Migraine is also shown to be correlated to haemorrhagic stroke, although studies do not demonstrate causation versus association, and further studies are warranted. There are also some rare genetic diseases such as cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy and others, which can cause both migraines and infarcts. On imaging, many migraineurs are found to have white matter changes similar to those seen in patients with stroke. These may be caused in part by alterations in resting cerebral blood flow and vasoconstrictor use. In treating patients with migraines, it is important to identify and modify any vascular risk factors such as hypertension, smoking, oral contraceptive pill use and lifestyle factors. Further studies will determine if more aggressive treatment of migraines can ultimately lead to fewer strokes in this population.
17Retinal migraine.PubMed
Brian M Grosberg, Seymour Solomon, Richard B Lipton
Curr Pain Headache Rep. 2005 Aug;9(4):268-71. doi: 10.1007/s11916-005-0035-2.
Retinal migraine is a primary headache disorder, clinically manifested by attacks of transient monocular visual loss associated with migraine headache. Although isolated reports suggest that retinal migraine is rare, it likely is under-recognized. Retinal migraine usually is reported in women of childbearing age who have a history of migraine with aura. It typically is characterized by negative monocular visual phenomena lasting less than 1 hour. More than half of reported cases with recurrent transient monocular visual loss subsequently experienced permanent monocular visual loss. Although the International Headache Society diagnostic criteria for retinal migraine require reversible visual loss, our findings suggest that irreversible visual loss is part of the retinal migraine spectrum, likely representing an ocular form of migrainous infarction.
18[Migraine and epilepsy].PubMed
Sadatoshi Tsuji
Rinsho Shinkeigaku. 2014;54(12):1003-5. doi: 10.5692/clinicalneurol.54.1003.
Migraine and epilepsy are both common episodic disorders that share many clinical features and underlying pathophysiological mechanisms. The comorbidity of these two conditions is well known. However, the temporal association between migraine and epilepsy is a controversial issue, since these two conditions may occur in numerous ways. Four types of association between headache and epileptic seizure are recognized: pre-ictal headache, headache as the expression of an epileptic manifestation, post-ictal headache, and inter-ictal headache. The classification of epilepsy by the International League Against Epilepsy did not refer to the epileptic headache. On the other hand, the International Classification of Headache Disorders, 3rd edition (ICHD-3) defines three entities: migraine aura-triggered seizure which sometimes referred to as migralepsy, hemicrania epileptica, and post-ictal headache. However, ICHD-3 mentions that there is a complex and bidirectional association between migraine and epilepsy. Most of the previous reports of migralepsy corresponded to occipital seizures that mimic migraine with aura. The term migralepsy has recently been criticized. Migraine and epilepsy share several pathophysiological mechanisms which involve neurotransmitters and iron channel dysfunctions. There is the hypothesis of a shared genetic susceptibility to migraine and epilepsy. Strong support of a shared genetic basis comes from familial hemiplegic migraine.
19[Menstrual migraine].PubMed
Kjersti Grøtta Vetvik, Michael Bjørn Russell
Tidsskr Nor Laegeforen. 2008 Nov 20;128(22):2575-8.
BACKGROUND: Migraine is twice as prevalent in women than men. Changing levels of estrogen appear to trigger menstrual migraine. This article reviews clinical characteristics, pathophysiology and treatment of menstrual migraine. MATERIAL AND METHODS: This review is based on literature retrieved from a non-systematic search of PubMed (up to January 2008) with the search terms "menstrual migraine" and "menstrual migraine and treatment". RESULTS AND INTERPRETATION: Pure menstrual migraine without aura is probably a distinct type of migraine caused by a fall in estrogen levels before the onset of menstruation. Women with menstrual migraine can receive prophylactic treatment in the perimenstrual period. There is no evidence that hormonal prophylaxis is more effective than non-hormonal. Because of an increased risk of thromboembolic events, hormonal treatment should only be given to women who have failed to respond to other treatment or to those who need hormonal treatment due to comorbidity.
20Familial hemiplegic migraine.PubMed
Daniela Pietrobon
Neurotherapeutics. 2007 Apr;4(2):274-84. doi: 10.1016/j.nurt.2007.01.008.
Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCNA1A, encoding the pore-forming alpha(1) subunits of the neuronal voltage-gated Ca2+ channels Ca(V)2.1 and Na+ channels Na(V)1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the alpha2 subunit of the Na+, K+ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHM1 knockin mice and of several FHM mutants in heterologous expression systems (12 FHM1, 8 FHM2, and 1 FHM3). These studies show the following: (1) FHM1 mutations produce gain-of-function of the Ca(V)2.1 channel and, as a consequence, increased Ca(V)2.1-dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phenomenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the alpha2 Na+,K+-ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na(V)1.5 (and presumably Na(V)1.1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K+ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K+ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.