The International Classification of Headache Disorders-3 (ICHD-3) classifies persistent aura without infarction (stroke) and migrainous infarction as two of the four reported complications of migraine, both of which are very rare. The other two reported complications of migraine include status migrainosus and migraine aura-triggered seizure, but these will not be discussed here1.
What Causes Migraine Aura?
In order to discuss persistent migraine aura without infarction or migrainous infarction, it is crucial to understand migraine pathophysiology, which involves a multitude of complex processes throughout the cortex, brainstem, and cerebral vasculature.
The pathophysiology of migraine has evolved from the vascular theory to the neurovascular theory of migraine. In other words, we now look at a migraine as an electrical event, not a vascular (blood vessel) related event. The older vascular theory proposed by Wolff viewed migraine as beginning with cerebral vasospasm causing focal ischemic (lack of blood flow) symptoms (aura) followed by extra and/or intracranial hyperperfusion (excess blood flow) from vasodilatation leading to the migraine pain. 2 This theory made good sense for how stroke or persistent neurological symptoms could develop, from the period of cerebral vasospasm and constriction. However, in later studies of migraine with aura, regional hypoperfusion developed before and outlasted focal neurologic symptoms, and this dissociation of time, perfusion changes and symptoms indicated that these neurologic symptoms were not caused by truly ischemic blood flow, but rather the apparent hypoperfusion is secondary to a disturbance in brain metabolism. 3-6
Lashley first described his own visual aura and hypothesized that the aura was due to a spreading abnormality migrating over the visual cortex at a rate of 3-5 mm per minute in 1941. 7 In 1944, Leão described spreading depression as a wave beginning with a brief neuronal burst associated with transient increased blood flow followed by a longer lasting neuronal electrical suppression with decreased blood flow in an animal model. 8-10
Subsequent studies confirmed this initial focal hyperemia followed by posteriorly to anteriorly spreading oligaemia (reduced blood flow) and regional cerebral blood flow reduction, which does not reach critical ischemic values, in a wave-like manner at approximately 2-5 mm per minute. This spreading regional cerebral blood flow reduction is independent of arterial territories, and does not cross cytoarchitectural borders or neuronal discontinuity such as the central sulcus or lateral sulcus, confirming impaired neuronal metabolism with subsequent regional cerebral blood flow reduction, rather than true ischemia. 3-6 This remains the basis for the now current neurovascular theory of migraine.
In other words, migraine aura is caused by an electrical wave spreading across the cortex of the brain moving at about 3 mm per minute (not by vasoconstriction as per the older vascular theory). At the front of this spreading electrical wave it causes hypermetabolism and an increase in blood flow. This hypermetabolism causes the “positive” migraine aura features (colors, flashing lights, kaleidoscope, shapes, zig-zags, tingling sensory changes, etc.). Following this electrical wave there is “neuronal depression” and hypometabolism, associated with a decrease in blood flow. This hypometabolism causes the “negative” migraine aura features (loss of vision, black spots, numbness, etc.).
Depending on where this wave spreads, you may get different aura symptoms; visual aura as it spreads across the occipital (visual) cortex, sensory/numbness/tingling as it spreads across the parietal (sensory) cortex, dysphasia (trouble speaking, slurred speech) as it spreads across the frontotemporal (speech) cortex, one sided weakness in hemiplegic migraine as it spreads across the frontal (motor) cortex, brainstem symptoms such as vertigo, tinnitus, double vision, hearing loss, imbalance, decreased level of consciousness, slurred speech (previously called basilar migraine, now called migraine with brainstem aura) as it spreads across the brainstem.
Most studies have been unable to show significant ischemic cerebral blood flow changes during migraine attacks. Results have shown alterations in cerebral blood volume, relative cerebral blood flow, and tissue mean transit time (MTT) in the grey matter of the occipital cortex contralateral (opposite) to the side of aura during an attack, while others have shown global cerebral blood flow increase, and others have shown hypoperfusion of the whole hemisphere, but never true ischemic hypoperfusion. 11-14 Notably, cerebral blood flow changes correlate poorly with migraine pain, and neurogenic inflammation in the trigemino-vascular system is suspected to be the primary cause of migraine pain, rather than arterial vasodilatation. 11,15
Persistent Migraine Aura Without Infarction (Visual Snow Syndrome, Status Aura)
The ICHD-3 defines persistent aura without infarction as aura symptoms persisting for 1 week or more without evidence of infarction on neuroimaging. It should occur in a patient with a history of migraine with aura and typical of previous auras except that one or more aura symptoms persist for 1 week or more. Neuroimaging must show no evidence of infarction, and symptoms are not better accounted for by another ICHD-3 diagnosis. The aura symptoms are often bilateral and may last for months or years. It is important to differentiate persistent aura without infarction from symptomatic aura as a result of cerebral migrainous infarction. Aura symptoms lasting more than 1 hour and less than 1 week are classified as probable migraine with aura.
There are two primary types of persistent migraine aura that are described. One is persistent primary visual disturbance in which the patients describe “visual snow” or “television static” in both visual fields in both eyes, and some report additional intermittent scotoma or oscillating lights. 16 The other is persistent migraine aura with typical aura, in which patients describe scotoma, fortification, or oscillation in one hemifield (one side of vision), and does not go away (sometimes also called status aura). 16
The specific pathophysiology of persistent migraine aura without infarction remains unknown, although several theories exist. Some of these theories include low cerebral magnesium levels, abnormal cerebral energy metabolism, greater cerebral reactivity of NMDA receptors to glutamate, lower threshold for triggering cortical spreading depression, low cortical preactivation due to thalamocortical hypoactivity, sustained hyperexcitability of the visual cortex without significant dynamic modulation, sustained cortical neuronal dysfunction, intracortical disinhibition, loss of inhibitory GABA-ergic interneurons resulting in a network imbalance leading to a reverberating cycle of cortical spreading depression (small cortical infarctions below MRI sensitivity in the occipital cortex has been one proposed mechanism), or a combination of any of these possibilities. 16-21
The evaluation for persistent migraine aura without infarction should focus on excluding intracranial pathology, primarily stroke, although other intracranial etiologies need to be excluded. Brain MRI scan is preferable with MRA of the brain and neck (to also assess the arteries), but if medically contraindicated, brain CT scan with CTA of the brain and neck (to assess the arteries) can be pursued. Contrast administration for either type of scan is suggested, although not mandatory. A detailed neuro-ophthalmologic examination is also required. Studies investigating other imaging modalities for persistent migraine aura without infarction, including FDG-PET, MR-PWI, and Tc99m-HMPAO-SPECT, have shown conflicting and inconsistent results.
Treatment for persistent aura without infarction is undefined, and generally based on medication trial and error. The literature reveals an extensive list of medications tried and failed, with most attempting to target neuronal hyperexcitability. Treatments and medications which have been assessed have included anticonvulsants (lamotrigine, topiramate, valproic acid, gabapentin, phenobarbital, phenytoin, carbamazepine), benzodiazepines (clonazepam, diazepam), antidepressants (amitriptyline, cymbalta, buspirone, fluoxetine, nortriptyline, sertraline, dothiepin), anti-hypertensive (atenolol, acetazolamide, flunarazine, metoprolol, propranolol, verapamil, nifedipine, nimodipine, furosemide), NSAIDs (acetylsalicylic acid, ibuprofen, flurbiprofen, diclofenac, indomethacin, naproxen) analgesics (acetaminophen, butalbital, codeine), and a variety of other medications (baclofen, citicholine, ergotamine, ketamine, cyproheptadine, methylphenidate, methylprednisolone, pizotifen, prochlorperazine, promethazine, sumatriptan, memantine). The vast majority of these medications have shown no evidence of benefit. 16 Of them, lamotrigine has shown the most evidence of benefit, while divalproex sodium, baclofen, sertraline, nifedipine, nimodipine, acetylsalicylic acid, and furosemide have reported varying degrees of benefit from complete to partial resolution of symptoms. 16
Abortive migraine options can include the gepants (Ubrelvy, Nurtec, Zavspret), ditans (Reyvow), neuromodulatory devices, and NSAIDs/over the counter analgesics. Triptans and ergots such as DHE (dihydroergotamine) should be avoided.
Migrainous Infarction (Stroke)
The ICHD-3 defines migrainous infarction as one or more migraine aura symptoms associated with an ischemic brain lesion in a correlating anatomical clinical territory demonstrated by neuroimaging. It should occur in a patient with a history of migraine with aura and typical of previous attacks except that one or more aura symptoms persists for more than 60 minutes, and it should not be better accounted for by another diagnosis. Clearly associating an ischemic stroke and a migraine attack in a migraine sufferer can be difficult. Cerebral infarction of other etiologies can coexist with migraine, can present with symptoms resembling migraine with aura, or cerebral infarction can occur during an attack of migraine with aura, and this is the only scenario that would be consistent with migrainous infarction.
Migrainous infarction occurs predominantly in the posterior circulation and in younger women. In the Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis (CAMERA) study, these infarct-like white matter lesions found in migraineurs (primarily in migraine with aura) were predominantly located in the posterior circulation, especially in the cerebellum. 22,23 However, these infarctions are not necessarily considered migrainous infarctions and the mechanisms are unclear.
The evaluation for migrainous infarction is similar to that of persistent migraine aura without infarction. By definition, an ischemic infarct in a correlating anatomic area to symptoms should be seen on MRI or CT of the brain. This warrants a further standard stroke evaluation, including imaging of the intra and extracranial vasculature (including carotid arteries), as well as cardiac evaluations beginning with transthoracic echocardiography. Electrocardiogram and telemetry should also be pursued to evaluate for paroxysmal arrhythmias such as atrial fibrillation.
Some theorized mechanisms of migrainous infarction include vasospasm, endothelial dysfunction, vascular endothelium-related hypercoagulability during cortical spreading depression and the aura phase, open patent foramen ovale, or genetic alterations of the wall of the small cerebral arterial vessel walls. 26-31
Treatment of migrainous infarction is the same as with any ischemic stroke acutely and preventively. The initial goal is to evaluate for potentially treatable etiologies (such as cardioembolic source) and treat accordingly. Otherwise, secondary stroke risk factor modifications are the goal and include antiplatelet therapy in combination with optimal control of blood pressure, hypertension, hyperlipidemia, diabetes, tobacco/smoking cessation, and healthy lifestyle changes.
Abortive migraine options can include the gepants (Ubrelvy, Nurtec ODT), ditans (Reyvow), neuromodulatory devices, and NSAIDs/over the counter analgesics, although triptans and ergots should be avoided.
Does Migraine With Aura Increase Your Risk of Stroke or Heart Attack?
Multiple studies have confirmed the association with increased stroke risk in women with migraine with aura. Women younger than age 45 who have migraine with aura, have a 2 fold increased risk of stroke. Notably, migraine without aura does not appear to have the same increased risk. This risk increases to 6 fold in the setting of oral contraceptive use containing estrogen, and more than 9 fold with combined smoking and oral contraceptive use. 24 Menstrual migraine and the use of hormonal therapy and birth control is discussed in more detail here.
Women who are smokers and have migraine with aura should consider estrogen containing oral contraception a contraindication. Oral contraceptive use in non-smoking women with migraine with aura is more controversial. The World Health Organization (WHO) and American College of Obstetrics and Gynecology (ACOG) suggest that in non-smoking women under age 35 with migraine with aura, there is an acceptable lower risk of oral contraceptive use. However, if they are over age 35, the risk is unacceptably higher and oral contraceptive use is contraindicated.
According to the International Headache Society (IHS), in non-smoking women with migraine with aura who are either younger or older than age 35, taking into account other risk factors should individualize the decision for oral contraceptives. 24 These would include ischemic heart disease, family history of early heart disease at a young age of less than 45 years old, heart disease with concern for emboli such as atrial fibrillation, uncontrolled hypertension, hyperlipidemia, diabetes, obesity, systemic disease associated with increased stroke (connective tissue disease, sickle cell, hypercoagulability), etc. In women with an increased risk of stroke, and especially with multiple vascular risk factors, non-estrogen methods of birth control such as progesterone-only forms of contraception should be recommended.
One study reported that after high blood pressure, migraine with aura was the second strongest single predictor of heart attack and strokes, ahead of diabetes, smoking, obesity, and family history of early heart disease. 25 This increased risk was not seen in migraine without aura. It is not necessarily thought that migraine with aura causes the stroke, but rather it is a marker for young women at a greater risk for cardiovascular disease (CVD). However, the reasons for these associations are unclear, likely multifactorial, and clearly need to be further defined. Traditional vascular risk factors such as hypertension, smoking, diabetes and hyperlipidemia still show the strongest contribution to cardiovascular disease, so these should be optimized, especially in those with migraine with aura to reduce risk of both heart disease and stroke. 25
A more recent larger follow up study evaluated the association of migraine with aura and other vascular risk factors with major CVD events (stroke, heart attack, death due to cardiovascular disease) in women aged 45 years or older. Women 45 years or older who had migraine with aura had a higher rate of CVD compared to women who had migraine without aura or no migraine. Basically, they looked at the likelihood of having heart attack or stroke if you have migraine with aura and compared the risk with a number of individual vascular risk factors which included diabetes, current smoker systolic blood pressure 160 mm Hg or higher, total cholesterol 280 mg/dL or higher, HDL cholesterol less than 40 mg/dL, triglycerides 194 mg/dL or higher, family history of heart attack prior to age 60 years old, and body mass index (BMI) of 30 or more.
Results showed that compared to having migraine with aura, only 2 other individual risk factors led to a higher incidence rate of major CVD; diabetes and current smoking. Women with migraine with aura had a similar risk of major CVD as those with high blood pressure, high total cholesterol, and family history of heart attack. Furthermore, adding migraine with aura to each individual risk factor led to a significantly increased risk of major CVD compared to having the vascular risk factor alone. These significant increases in CVD risk were associated specifically to migraine with aura, not migraine without aura.
These studies highlight the importance of optimizing medical treatments for vascular risk factors which lead to heart attack or stroke, especially in the setting of having migraine with aura.
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- Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2013;33:629-808.
- Wolff HG. Headache and Other Head Pain. New York: Oxford University Press, 1963.
- Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol 1981;9:344-52.
- Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain 1994;117 ( Pt 1):199-210.
- Lauritzen M, Skyhoj Olsen T, Lassen NA, Paulson OB. Changes in regional cerebral blood flow during the course of classic migraine attacks. Ann Neurol 1983;13:633-41.
- Lauritzen M, Olesen J. Regional cerebral blood flow during migraine attacks by Xenon-133 inhalation and emission tomography. Brain 1984;107 ( Pt 2):447-61.
- Lashley KS. Patterns of cerebral integration indicated by the scotomas of migraine. Arch Neurol Psych. 1941;46:331-339.
- Leao AAP. Spreading depression of activity in cerebral cortex. Journal of Neurophysiology 1944;7:359-390.
- Leao AAP, Morrison RS. Propagation of spreading cortical depression. Journal of Neurophysiology 1945;8:33-45.
- Leao AAP. Pial circulation and spreading depression of activity in the cerebral cortex. Journal of Neurophysiology 1944;7:391-396.
- Thomsen LL, Iversen HK, Olesen J. Cerebral blood flow velocities are reduced during attacks of unilateral migraine without aura. Cephalalgia 1995;15:109-16.
- Kobari M, Meyer JS, Ichijo M, Kawamura J. Cortical and subcortical hyperperfusion during migraine and cluster headache measured by Xe CT-CBF. Neuroradiology 1990;32:4-11.
- Sakai F, Meyer JS. Regional cerebral hemodynamics during migraine and cluster headaches measured by the 133Xe inhalation method. Headache 1978;18:122-32.
- Tfelt-Hansen PC, Koehler PJ. One hundred years of migraine research: major clinical and scientific observations from 1910 to 2010. Headache 2011;51:752-78.
- Moskowitz MA. Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology 1993;43:S16-20.
- Thissen S, Vos IG, Schreuder TH, Schreurs WM, Postma LA, Koehler PJ. Persistent migraine aura: new cases, a literature review, and ideas about pathophysiology. Headache 2014;54:1290-309.
- Relja G, Granato A, Ukmar M, Ferretti G, Antonello RM, Zorzon M. Persistent aura without infarction: decription of the first case studied with both brain SPECT and perfusion MRI. Cephalalgia 2005;25:56-9.
- Chen WT, Lin YY, Fuh JL, Hamalainen MS, Ko YC, Wang SJ. Sustained visual cortex hyperexcitability in migraine with persistent visual aura. Brain 2011;134:2387-95.
- Wang YF, Fuh JL, Chen WT, Wang SJ. The visual aura rating scale as an outcome predictor for persistent visual aura without infarction. Cephalalgia 2008;28:1298-304.
- Chronicle E, Mulleners W. Might migraine damage the brain? Cephalalgia 1994;14:415-8.
- Coppola G, Parisi V, Di Lorenzo C, et al. Lateral inhibition in visual cortex of migraine patients between attacks. J Headache Pain 2013;14:20,2377-14-20.
- Kruit MC, van Buchem MA, Launer LJ, Terwindt GM, Ferrari MD. Migraine is associated with an increased risk of deep white matter lesions, subclinical posterior circulation infarcts and brain iron accumulation: the population-based MRI CAMERA study. Cephalalgia 2010;30:129-36.
- Kruit MC, Launer LJ, Ferrari MD, van Buchem MA. Infarcts in the posterior circulation territory in migraine. The population-based MRI CAMERA study. Brain 2005;128:2068-77.
- Tepper SJ, Tepper DE. The Cleveland Clinic Manual of Headache Therapy, 2nd ed. . Switzerland: Springer International Publishing, 2014.
- Kurth T, Bubes V, Buring J. Relative Contribution of Migraine with Aura to Cardiovascular Disease Occurrence in Women. Neurology 2013;80.
- Pezzini A, Del Zotto E, Giossi A, et al. The migraine-ischemic stroke relation in young adults. Stroke Res Treat 2010;2011:304921.
- Pezzini A, Del Zotto E, Giossi A, Volonghi I, Grassi M, Padovani A. The migraine-ischemic stroke connection: potential pathogenic mechanisms. Curr Mol Med 2009;9:215-26.
- Kurth T, Chabriat H, Bousser MG. Migraine and stroke: a complex association with clinical implications. Lancet Neurol 2012;11:92-100.
- Kurth T. Migraine and ischaemic vascular events. Cephalalgia 2007;27:965-75.
- Tietjen EG. Migraine and ischaemic heart disease and stroke: potential mechanisms and treatment implications. Cephalalgia 2007;27:981-7.
- Bousser MG, Welch KM. Relation between migraine and stroke. Lancet Neurol 2005;4:533-42.