Pathologic Differences Between Migraine With or Without Aura

Aura has long been a perplexing issue in migraine. Primarily viewed as a prodromal sign of migraine in some patients some of the time, aura has been largely overlooked in clinical trials that tend to enroll patients with migraine with and without aura.¹ However, new evidence increasingly points to migraine with aura as a separate entity from migraine without aura, with important pathologic differences.

The most recent definition of migraine aura by the International Classification of Headache Disorders-3 (ICHD-3) is from 2018,² and cites “recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory, or other central nervous system symptoms that usually develop gradually and are usually followed by headache and associated migraine symptoms.”

As many as one-third of patients with migraine may experience aura (prevalence estimated at 20%-40% of all people with migraine), although most do not experience aura with every migraine.^1,3 The clinical manifestation of auras varies among patients, and between attacks in the same patient. Most (99%) patients experience visual distortions at least some of the time, as well as sensory, speech/language, motor function symptoms, and alterations of cortical function.¹

Migraine with aura has not been well studied compared with migraine without aura, and participants with both types of migraine are generally accepted into the same clinical trials.¹ This may be in large part because there is a lower prevalence of migraine with aura, but also because of the difficulty of examining the aura event itself.⁴

Although patients with aura are more likely to be referred for computed tomography scanning, images rarely capture aura, as researchers have yet to find a dependable means to predict or trigger the phenomenon.^5-7 In addition, the short duration of auras (usually lasting <60 minutes) prevents the opportunity to obtain a scan when the event occurs.⁴

Among imaging studies that have been done, white matter abnormalities were detected at 4 times the rates in patients with total migraine compared with the general population, but no significant differences in structural brain changes were observed between migraine with aura and migraine without aura.¹ Early studies did show differences in blood flow dynamics between the 2 types of migraines.^4,7 In 1990, following 10 years of study of the aura phenomenon, Olesen et al⁷ showed a posterior drop in regional cerebral blood flow on one side of the brain that preceded or accompanied symptoms of aura, followed by headache.

In recent years, however, a spate of investigations and reviews have begun to differentiate features of migraine with aura from those of migraine without aura, with several other important findings¹:

• Migraine with aura typically has a more dramatic presentation of multiple clinical manifestations than the more common migraine without aura.⁴
• Migraine with aura is associated with a 2-fold higher risk for stroke, while migraine without aura is not.¹
• Imaging studies show changes to structural brain function are more pronounced in migraine with aura.¹
• Cerebral blood flow patterns may differ between migraine with aura or without.^1,7
• There are significant differences in therapeutic response to acute and preventive therapies.¹

Studies also suggest that auras that accompany migraines may not be a singular entity, but instead represent a broad spectrum of events from various pathophysiologies.⁴ Different manifestations include prolonged auras; those with somatosensory, dysphasic, or motor features; and those that are primarily visual.⁴

Timing of the aura also varies. Most occur prior to the onset of migraine headache pain, but the types of migraines may also start simultaneously, or there may be no headache at all.^1,7 Triggers for the attack are less likely to be reported when aura occurs.¹ These differences in timing suggest that cortical spreading depression might be a mechanism for aura, but not necessarily a mechanism for all migraines.^1,7

Patent foramen ovale, a congenital heart defect, occurs with high frequency (79%) in patients with concomitant migraine and cryptogenic stroke.⁸ This is exacerbated in people with migraine who have frequent auras, increasing the frequency to 93%.^1,9 Surgical closure of patent foramen ovale as a preventive therapy was shown to be effective in reducing the number of migraine days with aura, but did not reduce the number of days with migraine overall.¹⁰

The current recommended treatments for both types of migraine are the same, although the responses to therapy in migraine with aura are significantly lower than in migraine without aura.¹

In clinical trials, triptans, a first-line acute therapy for migraine, were not found to be effective when given during the prodromal stage when aura typically occurs. While aura was slightly diminished in duration from an average of 30 minutes to 25 minutes by the injection of sumatriptan, this modest difference was not statistically significant when compared with placebo.¹

Among newer preventive therapies, memantine and lamotrigine have both demonstrated efficacy against migraine with aura as well as migraine without aura.¹ Because it has multiple mechanisms of action, topiramate has shown good potential in reducing the frequency of both migraine with and without aura.¹ Tonabersat has been shown to be effective only against migraine with aura (ClinicalTrials.gov identifier: NCT00332007).^1,9

A range of important differences between migraine with and without aura are now being explored, adding evidence to support the distinction of each as a separate entity. Further investigation into differences in pathophysiologic mechanisms may help drive new therapies aimed at reducing the frequency of migraine with aura.

References

1. Hansen JM, Charles A. Differences in treatment response between migraine with aura and migraine without aura: lessons from clinical practice and RCTs. J Headache Pain. 2019;20:96.

2. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38:1-211.

3. Charles A. The migraine aura. Continuum (Minneap Minn). 2018;24(4, Headache):1009-1022.

4. Coppola G, Di Lorenzo C, Parisi V, Lisicki M, Serrao M, Pierelli F. Clinical neurophysiology of migraine with aura. J Headache Pain. 2019;20:42.

5. Vijiaratnam N, Barber D, Lim KZ, et al. Migraine: Does aura require investigation? Clin Neurol Neurosurg. 2016;148:110-114.

6. Hadjikhani N, Vincent M. Neuroimaging clues of migraine aura. J Headache Pain. 2019;20:32.

7. Olesen J, Friberg L, Olsen TS, et al. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol. 1990;28:791-798.

8. West BH, Noureddin N, Mamzhi Y, et al. Frequency of patent foramen ovale and migraine in patients with cryptogenic stroke. Stroke. 2018;49(5):1123-1128.

9. Hauge AW, Asghar MS, Schytz HW, Christensen K, Oleson J. Effects of tonabersat on migraine with aura: a randomised, double-blind, placebo-controlled crossover study. Lancet Neurol. 2009;8:718-723.

10. Charles A, Hansen JM. Migraine aura: new ideas about cause, classification, and clinical significance. Curr Opin Neurol. 2015;28:255-260.