Is Migraine a Progressive Brain Disease?

In this issue of THE JOURNAL, Kruit and colleagues¹ provide important new data on the prevalence of brain infarction and white matter lesions in persons with migraine. The authors systematically recruited individuals with migraine with aura and migraine without aura as well as group-matched controls without migraine from the general Dutch population. By using population surveys, the authors identified a representative sample of migraine cases, addressing concerns about selection bias in earlier studies.^{2 - 4} An appropriate population control group without migraine was recruited from the screened sample. The use of 3-mm magnetic resonance imaging (MRI) sections improved lesion detection, and imaging studies were interpreted masked to case status, minimizing bias in the assessment of radiographic findings. Demographic factors, cardiovascular diseases, headache features, and treatment patterns were carefully assessed so that these potential confounders and effect modifiers could be taken into account.

Using these rigorous methods, the authors found that individuals with migraine had an 8% prevalence of radiographic infarction in comparison with 5% prevalence among controls (P = .23). The association was strongest for posterior circulation infarcts (5.4% vs 0.7%; P = .02), a location implicated in earlier studies of stroke in persons with migraine.^{5 - 6} The cerebellum, known to be vulnerable in familial hemiplegic migraine, was a site of predilection for infarction.^{7 - 8} The rate of posterior circulation infarction was particularly elevated in individuals with migraine with aura compared with those with migraine without aura (8.1% vs 2.2%; P = .03).

The authors suggest a number of plausible biological mechanisms to account for the increased rate of posterior circulation infarction, particularly among persons with migraine with aura. Although their radiographic appearance is compatible with stroke, these cerebellar lesions did not have clinical correlates on standard neurological examination. Using more sensitive measures, investigators have shown cerebellar dysfunction in persons with migraine.⁹ Direct clinical assessment of migraineurs from the population with and without cerebellar MRI lesions using sensitive measures of cerebellar dysfunction would strengthen the results.

Subclinical posterior circulation stroke and diffuse white matter lesion load increased with frequency of migraine, confirming recent findings from a clinic-based study.¹⁰ This association with migraine frequency raises the possibility that the MRI findings may reflect cumulative brain insults due to repeated migraine attacks. If this interpretation is correct, migraine may sometimes be a cause of progressive damage to the brain. Alternatively, there may be a confounding factor associated with both frequent migraine and stroke.

In another recent imaging study using different methods, Welch and colleagues¹¹ showed that elevations in iron levels in the periaqueductal gray matter increased with disease duration in persons with migraine and chronic daily headache. They suggested that iron deposition may reflect progressive neuronal damage related to recurrent migraine attacks.

Imaging results suggesting progressive brain changes in migraine are particularly interesting in light of a recent epidemiologic study that showed that a subgroup of persons with headache may have a clinically progressive disorder. In a population sample, Scher et al¹² showed that over the course of 1 year, 3% of individuals with episodic headache (headache frequency 2-104 days per year) progressed to chronic daily headache (attack frequency >180 days per year). Risk factors for progression included migraine headaches, higher attack frequency, and elevated body mass index, among other factors.¹² This population-based result is compatible with findings from a case-control study and numerous clinic-based observational studies.¹³ In addition to progression of disease, some investigators reported that two thirds of patients with migraine develop sensitization, arguably a form of progression of the attack.^{14 - 15}

These data have implications for current concepts of migraine as a disease; migraine should be conceptualized not just as an episodic disorder but as a chronic-episodic and sometimes chronic progressive disorder. With this shift in conceptualization, the goals of treatment may also shift. Preventing disease progression in migraine has already been added to the traditional goals of relieving pain and restoring patients' ability to function.^{16 - 17} If the brain lesions demonstrated by Kruit et al¹ have a significant clinical correlate, preventing the accumulation of brain lesions may become an additional goal of treatment. Emerging treatment strategies to prevent disease progression, including risk factor modification, preventive therapies, and the early use of acute treatments, are an important focus for future investigation.^{12 ,17}