The Complex Interplay of Migraine: Pathophysiology, Stroke Risk, and Evolving Management Strategies

Abstract

Migraine, a prevalent neurological disorder characterized by recurrent headaches and associated symptoms, presents a significant global health burden. Beyond the immediate impact of acute attacks, growing evidence suggests a complex interplay between migraine and various comorbidities, including an increased risk of stroke, particularly in specific migraine subtypes and patient populations. This research report delves into the multifaceted pathophysiology of migraine, exploring the intricate mechanisms underlying its different subtypes and their potential links to stroke risk. It critically examines the proposed pathophysiological mechanisms, such as inflammation, endothelial dysfunction, platelet activation, and the role of patent foramen ovale (PFO), in mediating the migraine-stroke association. Furthermore, it evaluates the latest advancements in migraine management and prevention strategies, assessing whether specific treatments might influence stroke risk. Finally, it discusses the potential utility of screening protocols for migraine sufferers, especially those at heightened risk of stroke, aiming to guide clinical decision-making and improve patient outcomes.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Migraine is a complex neurological disorder affecting approximately 12% of the global population, characterized by recurrent, often debilitating, headaches. While the classic symptom is a unilateral, throbbing headache, migraine presents with a diverse range of associated symptoms, including nausea, vomiting, photophobia, and phonophobia. The International Headache Society (IHS) classifies migraine into distinct subtypes, primarily migraine without aura (MO) and migraine with aura (MA). Aura symptoms, typically preceding or accompanying the headache phase, involve transient focal neurological disturbances, such as visual, sensory, or motor deficits.

Beyond the immediate burden of acute migraine attacks, the condition has been linked to a variety of comorbid conditions, including cardiovascular diseases. Of particular concern is the association between migraine, especially MA, and an increased risk of ischemic stroke. This association, however, is not straightforward and appears to be influenced by factors such as age, sex, migraine subtype, and the presence of other cardiovascular risk factors. Understanding the complex interplay between migraine pathophysiology and stroke risk is crucial for developing effective preventive strategies and improving patient outcomes. This report aims to provide a comprehensive overview of the current understanding of migraine pathophysiology, its association with stroke, and the implications for clinical management.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Pathophysiology of Migraine: A Multifaceted Perspective

The precise pathophysiology of migraine remains incompletely understood, but significant progress has been made in recent decades. The current understanding integrates several key elements, including neuronal dysfunction, vascular changes, inflammation, and genetic predisposition.

2.1. Cortical Spreading Depression (CSD)

CSD, a slowly propagating wave of neuronal and glial depolarization followed by prolonged suppression, is widely considered a key event in MA. This phenomenon, first described by Leão in 1944, originates in the occipital cortex and spreads anteriorly. CSD triggers the release of various neuroactive substances, including glutamate, potassium ions, and nitric oxide (NO), which can activate trigeminal nerve endings and lead to the release of vasoactive neuropeptides, such as calcitonin gene-related peptide (CGRP). Although CSD is most consistently associated with MA, evidence suggests it may also play a role in MO, albeit through different mechanisms or with more subtle manifestations.

2.2. Trigeminal Vascular System Activation

The trigeminal vascular system, comprising the trigeminal nerve and its projections to intracranial blood vessels, plays a crucial role in migraine pathogenesis. Activation of trigeminal nerve endings releases vasoactive neuropeptides like CGRP, substance P, and neurokinin A, causing vasodilation of intracranial arteries, dural inflammation, and mast cell degranulation. CGRP, in particular, has emerged as a key target for migraine therapy, with the development of CGRP monoclonal antibodies and gepants (CGRP receptor antagonists).

2.3. Central Sensitization

Central sensitization, a state of neuronal hyperexcitability in the central nervous system, contributes to the chronification of migraine and the development of cutaneous allodynia (pain elicited by normally non-painful stimuli). Repeated migraine attacks can lead to long-term potentiation of pain pathways, making the brain more sensitive to future triggers and pain signals. Central sensitization involves changes in both neuronal excitability and synaptic transmission in brain regions involved in pain processing, such as the trigeminal nucleus caudalis, thalamus, and cortex.

2.4. Genetic Factors

Migraine has a strong genetic component, with a significant heritability estimate. Several genes have been implicated in familial hemiplegic migraine (FHM), a rare subtype of migraine with aura characterized by motor weakness. These genes encode ion channels and ATPases, suggesting that disturbances in neuronal excitability and ion transport can contribute to migraine pathogenesis. While FHM genes are relatively rare in common migraine, genome-wide association studies (GWAS) have identified numerous common genetic variants associated with increased migraine risk. These variants often involve genes involved in neuronal excitability, synaptic function, and vascular regulation.

2.5. Inflammation

Inflammation plays a critical role in migraine pathophysiology. During a migraine attack, inflammatory mediators, such as cytokines (e.g., TNF-α, IL-1β, IL-6), are released in the meninges and brain parenchyma. These cytokines can activate trigeminal nerve endings, sensitize central pain pathways, and contribute to vasodilation and edema. Mast cells, which are abundant in the meninges, release histamine and other inflammatory mediators, further amplifying the inflammatory response. The role of inflammation in migraine has led to the investigation of anti-inflammatory agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, for migraine treatment.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Migraine and Stroke Risk: Exploring the Association

Epidemiological studies have consistently demonstrated an association between migraine, particularly MA, and an increased risk of ischemic stroke. The magnitude of this risk, however, varies across studies and is influenced by factors such as age, sex, migraine subtype, and the presence of other cardiovascular risk factors.

3.1. Epidemiological Evidence

Meta-analyses of observational studies have reported a modestly increased risk of ischemic stroke in individuals with migraine, with the risk being higher for those with MA compared to those with MO. Women with MA appear to be at particularly elevated risk, especially those using hormonal contraceptives or who smoke. The absolute risk of stroke in migraine sufferers, however, remains relatively low, especially in the absence of other risk factors.

3.2. Proposed Mechanisms Linking Migraine and Stroke

Several mechanisms have been proposed to explain the association between migraine and stroke. These include:

• Cortical Spreading Depression (CSD): CSD can cause transient cerebral hypoperfusion, potentially leading to ischemic events in vulnerable brain regions. Furthermore, CSD can activate inflammatory pathways and promote platelet aggregation, increasing the risk of thromboembolism.
• Endothelial Dysfunction: Migraineurs, particularly those with MA, may exhibit endothelial dysfunction, characterized by impaired vasodilation and increased platelet aggregation. Endothelial dysfunction can promote the formation of atherosclerotic plaques and increase the risk of thrombotic events.
• Hypercoagulability: Some studies have reported evidence of hypercoagulability in migraineurs, with elevated levels of procoagulant factors and reduced levels of anticoagulant factors. This prothrombotic state may increase the risk of both arterial and venous thromboembolism.
• Patent Foramen Ovale (PFO): PFO, a persistent opening between the right and left atria, is more prevalent in migraineurs, particularly those with MA. PFO can allow paradoxical embolism, where thrombi from the venous system bypass the pulmonary circulation and enter the arterial circulation, potentially causing stroke.
• Inflammation: Systemic and cerebral inflammation associated with migraine could contribute to stroke risk by damaging blood vessels and promoting atherosclerosis.

3.3. Migraine with Aura and Stroke: A Closer Look

The association between migraine and stroke is particularly strong for MA. The presence of aura symptoms, reflecting cortical dysfunction and CSD, may represent a more severe form of migraine with greater propensity for vascular complications. Visual aura, the most common type of aura, has been specifically linked to an increased risk of ischemic stroke.

3.4. Migraine, PFO, and Stroke

The association between migraine, PFO, and stroke has been the subject of intense research. PFO is more prevalent in individuals with MA, and studies have suggested that PFO closure may reduce migraine frequency and severity in selected patients. While PFO closure has been shown to reduce the risk of recurrent stroke in patients with cryptogenic stroke (stroke of unknown cause) and PFO, its efficacy in preventing stroke specifically in migraineurs with PFO remains uncertain. The exact mechanism by which PFO contributes to migraine and stroke risk is not fully understood, but it is likely related to paradoxical embolism of microthrombi or vasoactive substances.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Management Strategies for Migraine and Stroke Risk Mitigation

The management of migraine aims to reduce the frequency, severity, and duration of attacks, improve quality of life, and prevent the development of chronic migraine. Given the potential association between migraine and stroke, management strategies should also consider stroke risk mitigation.

4.1. Lifestyle Modifications

Lifestyle modifications, such as regular exercise, stress management, adequate sleep, and avoidance of migraine triggers, are important components of migraine management. These measures can reduce the frequency and severity of attacks, potentially indirectly reducing stroke risk.

4.2. Acute Treatment

Acute treatments for migraine aim to abort or alleviate the symptoms of an ongoing attack. These include:

• NSAIDs: NSAIDs, such as ibuprofen and naproxen, can be effective for mild to moderate migraine attacks. However, prolonged use of NSAIDs can increase the risk of gastrointestinal bleeding and cardiovascular events.
• Triptans: Triptans, selective serotonin 5-HT1B/1D receptor agonists, are highly effective for acute migraine treatment. They work by constricting intracranial blood vessels and inhibiting the release of vasoactive neuropeptides. However, triptans are contraindicated in patients with a history of ischemic heart disease or stroke due to their vasoconstrictive effects. Furthermore, overconsumption of triptans can lead to medication-overuse headache (MOH).
• Gepants: Gepants, CGRP receptor antagonists, are a newer class of acute migraine medications that do not have vasoconstrictive effects and may be safer for patients with cardiovascular risk factors. Several gepants are approved for acute migraine treatment, including rimegepant, ubrogepant, and atogepant.
• Ditans: Ditans, selective 5-HT1F receptor agonists, are another class of acute migraine medications that do not cause vasoconstriction. Lasmiditan is currently the only approved ditan for acute migraine treatment.

4.3. Preventive Treatment

Preventive treatments for migraine aim to reduce the frequency and severity of attacks. These include:

• Beta-blockers: Beta-blockers, such as propranolol and metoprolol, are commonly used for migraine prevention. They work by blocking beta-adrenergic receptors, reducing neuronal excitability and blood pressure. However, beta-blockers are contraindicated in patients with asthma or severe bradycardia.
• Tricyclic Antidepressants (TCAs): TCAs, such as amitriptyline, are effective for migraine prevention. They work by modulating neurotransmitter levels and reducing central sensitization. However, TCAs can cause side effects such as dry mouth, constipation, and weight gain.
• Antiepileptic Drugs (AEDs): AEDs, such as topiramate and valproate, are used for migraine prevention. Topiramate works by blocking sodium channels and enhancing GABAergic transmission, while valproate works by increasing GABA levels and modulating sodium and calcium channels. Both topiramate and valproate are teratogenic and should be avoided in women of childbearing potential unless effective contraception is used.
• CGRP Monoclonal Antibodies: CGRP monoclonal antibodies, such as erenumab, fremanezumab, galcanezumab, and eptinezumab, are a highly effective and well-tolerated class of migraine preventive medications. They work by blocking CGRP or its receptor, preventing the activation of trigeminal nerve endings and reducing inflammation. CGRP monoclonal antibodies have shown significant efficacy in reducing migraine frequency and disability.
• OnabotulinumtoxinA (Botox): OnabotulinumtoxinA is approved for the prevention of chronic migraine. It works by inhibiting the release of neurotransmitters, including CGRP, from trigeminal nerve endings.

4.4. Specific Considerations for Migraineurs at High Stroke Risk

For migraineurs at high stroke risk, such as those with MA, PFO, or other cardiovascular risk factors, specific management strategies should be considered. These include:

• Avoidance of Hormonal Contraceptives: Women with MA should avoid using estrogen-containing hormonal contraceptives due to the increased risk of stroke.
• Smoking Cessation: Smoking significantly increases the risk of stroke in migraineurs and should be strongly discouraged.
• Management of Cardiovascular Risk Factors: Aggressive management of hypertension, hyperlipidemia, and diabetes is crucial for reducing stroke risk in migraineurs.
• Consideration of PFO Closure: In selected patients with MA and PFO, PFO closure may be considered, particularly if they have a history of cryptogenic stroke or transient ischemic attack (TIA). However, the decision to perform PFO closure should be individualized based on the patient’s risk profile and the potential benefits and risks of the procedure.
• Careful Selection of Acute and Preventive Medications: Triptans should be used with caution in migraineurs with cardiovascular risk factors. Gepants and ditans may be safer alternatives for acute treatment. Preventive medications with cardiovascular benefits, such as beta-blockers, may be preferred in patients with hypertension.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Screening Protocols for Migraine Sufferers

Given the potential association between migraine and stroke, the question arises whether specific screening protocols should be implemented for migraine sufferers, particularly those at heightened risk. However, routine screening for stroke risk factors in all migraineurs is not currently recommended due to the relatively low absolute risk of stroke and the lack of evidence that widespread screening would improve outcomes. Nevertheless, targeted screening may be appropriate for specific subgroups of migraine sufferers.

5.1. Risk Stratification

Risk stratification is crucial for identifying migraineurs who may benefit from further evaluation and management. Factors that should be considered in risk stratification include:

• Migraine Subtype: Patients with MA are at higher risk of stroke compared to those with MO.
• Age: The risk of stroke increases with age.
• Sex: Women with MA are at particularly elevated risk.
• Cardiovascular Risk Factors: The presence of hypertension, hyperlipidemia, diabetes, smoking, or obesity significantly increases stroke risk.
• Family History of Stroke: A family history of stroke increases the risk of stroke.
• Presence of PFO: Patients with MA and PFO may be at higher risk of stroke.

5.2. Potential Screening Tools

Potential screening tools for migraine sufferers at high stroke risk include:

• Blood Pressure Measurement: Regular blood pressure monitoring is essential for detecting hypertension.
• Lipid Profile: Lipid profile testing can identify hyperlipidemia.
• Blood Glucose Testing: Blood glucose testing can detect diabetes.
• Echocardiography with Bubble Study: Echocardiography with bubble study can detect PFO.
• Transcranial Doppler with Bubble Study: Transcranial Doppler with bubble study can also detect PFO.
• Carotid Ultrasound: Carotid ultrasound can detect carotid artery stenosis.

5.3. Considerations for Implementation

Implementing screening protocols for migraine sufferers requires careful consideration of the potential benefits and risks, as well as the cost-effectiveness of screening. Screening should be targeted to individuals at high risk and should be accompanied by appropriate counseling and management strategies.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Future Directions and Conclusion

The complex interplay between migraine and stroke continues to be an area of active research. Future studies should focus on:

• Elucidating the mechanisms underlying the migraine-stroke association: Further research is needed to clarify the specific mechanisms by which migraine increases stroke risk, including the role of CSD, inflammation, endothelial dysfunction, and PFO.
• Identifying biomarkers for stroke risk in migraineurs: Identifying biomarkers that can predict stroke risk in migraineurs would allow for more targeted screening and management strategies.
• Evaluating the efficacy of PFO closure in preventing stroke in migraineurs: Randomized controlled trials are needed to determine the efficacy of PFO closure in preventing stroke specifically in migraineurs with PFO.
• Developing novel therapies that target both migraine and stroke risk: Developing novel therapies that can simultaneously reduce migraine frequency and stroke risk would be a significant advance in the management of this complex condition.

In conclusion, migraine is a complex neurological disorder with a potential association with stroke, particularly in specific subtypes and patient populations. Understanding the pathophysiology of migraine and its potential links to stroke is crucial for developing effective management strategies. Risk stratification and targeted screening may be appropriate for migraine sufferers at high stroke risk. Future research is needed to further elucidate the mechanisms underlying the migraine-stroke association and to develop novel therapies that can simultaneously reduce migraine frequency and stroke risk.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

References

1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211.
2. Kurth T, et al. Migraine and risk of cardiovascular disease in women. JAMA. 2016;316(4):404-412.
3. Goadsby PJ, et al. Pathophysiology of migraine: a disorder of sensory processing. Lancet Neurol. 2017;16(8):613-622.
4. Lauritzen M. Cortical spreading depression as a target for migraine therapy. Brain. 1994;117(Pt 1):1-11.
5. Moskowitz MA. Neurogenic versus vascular mechanisms of migraine headache. Neurology. 1993;43(3 Suppl 3):S26-S30.
6. Dodick DW. Migraine. Lancet. 2018;391(10127):1315-1330.
7. Eikermann-Haerter K, et al. Inflammation and migraine—new insights and therapeutic options. J Headache Pain. 2018;19(1):103.
8. Ligthart L, et al. Genome-wide association study identifies new susceptibility loci for migraine. Nat Genet. 2016;48(10):1231-1236.
9. Spector JT, et al. Migraine headache and the risk of stroke in women. Stroke. 2010;41(8):1673-1679.
10. Etminan M, et al. Risk of ischemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ. 2005;330(7482):63-65.
11. Lipton RB, et al. Patent foramen ovale and migraine: a systematic review of the literature. Headache. 2005;45(8):1062-1074.
12. Wilmshurst P, et al. Role of patent foramen ovale in migraine. J Am Coll Cardiol. 2013;62(1):68-77.
13. Barbanti P, et al. Gepants for migraine: a systematic review and meta-analysis. J Headache Pain. 2021;22(1):25.
14. Tepper SJ. CGRP monoclonal antibodies for migraine prevention. Lancet. 2017;390(10095):729-730.