Migraine Linked to Structural Brain Changes

Pauline Anderson

August 28, 2013

A new literature review confirms that compared with patients without migraine, those with migraine have more white matter abnormalitiies (WMAs), infarct-like lesions (ILLs), and volumetric changes in gray and white matter regions of the brain, although the cllnical and functional significance of these lesions is still uncertain.

The analysis showed that the association between migraine and structural changes in the brain is stronger among those who experience migraine with aura.

The results challenge the widely accepted notion that migraine is a benign primary headache with no long-term consequences or sequelae for the brain.

"Our study, based on a systematic review and meta-analysis, suggests the opposite: that this primary headache disorder may permanently change the brain structure," said author Sait Ashina, MD, headache program director, Beth Israel Medical Center, and assistant professor, neurology and anesthesiology, Albert Einstein College of Medicine, New York, New York.

However, Dr. Ashina cautioned that not all the evidence is in yet and that prospective longitudinal studies are needed to confirm the influence of migraine on brain structure.

Dr. Sait Ashina

The study is published online August 28 in Neurology.

From a literature search, investigators identified 13 clinic-based and 6 population-based studies (4 studies were based on the same cohort). Clinic-based and population-based studies provide complementary perspectives on the potential influence of migaine on brain structrures, the authors write.

Dr. Ashina and colleagues summarized the data on the association of migraine with aura (MA) and migraine without aura (MO) on 3 forms of structrural brain abnormalities: WMAs, ILLs, and volumetric changes to white and gray matter brain regions.

WMAs, Silent ILLs, Volumetric Changes

The reported prevalance rates of WMAs in migraineurs ranges from 4% to 59%. The meta-analysis showed that WMAs were 1.68 times more likely to be associated with MA (odds ratio [OR], 1.68; 95% confidence interval [CI], 1.07 - 2.65; P = .03) and 1.34 times more likely to be associated with MO (OR, 1.34; 95% CI, 0.96 - 1.87), although the result for migraine without aura did not reach statistical significance (P = .08).

The pathogenesis and clinical significance of these abnormalities related to migraine are not known, said Dr. Ashina. "Basically it is not clear how and why these lesions develop, what they are, and what long-term consequences they have for individuals with migraine."

WMAs have been shown pathologically to have gliosis, demyelination, and loss of axons, which could be due to microvascular damage, said Dr. Ashina. These abnormalities have also been reported to increase with migraine frequency, which could be a form of anatomic progression of migraine, he said.

The study found that the association of ILLs was greater for MA (OR, 1.44; 95% CI, 1.02 - 2.03; P = .04) than for MO but did not find an association for MA (P = .52) and MO (P = .08) when compared with controls. The analysis here, however, is difficult to interpret, in part because it included only 2 studies, said the authors.

The analysis demonstrated that brain volume changes, such as reduced gray matter density, were more common in people with migraine with and without aura than those with no migraine.

Seven clinic-based studies showed predilection sites of volumetric changes in the brain. The sites of volume loss included the bilateral insula, frontal/prefrontal, temporal, parietal, and occipital cortices; anterior cingulate cortex; basal ganglia; and cerebellum. On the other hand, volume in other sites increased, including the dorsolateral pons and periaqueductal gray. Some of these sites are involved in pain control or in pain regulation.

Volumetric changes may reflect a complication of frequent migraine attack, but further studies are required to confirm this hypothesis, said the authors. The clincial significance of these changes is unclear, they said.

It doesn't appear that structural brain changes affect cognition. In this regard, "so far, it looks like the studies have been negative," said Dr. Ashina.

It's not clear why the association between migraine and structural brain changes is stronger when the headaches involve aura. "At this point, we don’t know for sure why that is, but we do know that migraine with aura has been associated with strokes," which could affect pathology, noted Dr. Ashina.

"What we’re finding is purely descriptive, but it's interesting, and it's something we need to look at in future. Do these patients, for example, have more prolonged headaches, are their headaches more severe, and are these headaches being addressed properly?"

Interpretation Difficult

Results of this analysis should be interpereted with caution because the literature on structural MRI in migraine is difficult to interpret, said the authors.

The analysis is also limited in that the included studies vary widely in sample size, patient selection (age, sex, vascular risk factors, antimigraine therapy), headache characteristics (migraine subtype, attack frequency, disease duration), test methods, timing of study, and data interpretation. As well, inadequately or unmeasured confounding is possible, although the authors did measure and adjust for many such confounders.

Another limitation is that although the studies, which were mostly cross-sectional, demonstrate associations between migraine and brain structures, they don’t reveal the directionality of the associations.

Clinic-based studies that recruit from specialty care setttings may not be representative of migraineurs because only a minority of patients — typically those with more severe attack, more frequent attacks, and more comorbid conditions — are treated in such settings, said Dr. Ashina. Population-based studies circumvent selection bias and are readily generalizable, athough the questionnaires upon which they’re based may not garner 100% participation, he said.

Although the study suggests that migraine may be a risk factor for structural changes in the brain, more studies are needed to assess any longitudinal changes in brain function. Important variables to study include migraine attack frequency and length of the disease, said Dr. Ashina.

Guidelines from the American Academy of Neurology and US Headache Consortium suggest that patients with migraine who have a normal neurologic examination don’t need routine MRI of the brain. MRI is recommended only for those with atypical headache; a recent change in headache pattern; other symptoms, such as seizures; or focal neurologic signs or symptoms.

According to Dr. Ashina, the 1-year prevalence of migraine in the United States is approximately 13%. Women are affected more than men; the 1-year prevalence is 18.2% in women and 6.5% in men. Unfortunately, migraine receives little attention from healthcare practitioners and policymakers and therefore remains a widely underdiagnosed and undertreated condition, he said.

Challenging Issues

Asked to comment, Peter J. Goadsby, MD, PhD, director, University of California San Francisco Headache Center, said the new data are important for both physicians and patients, but from a pathophysiologic perspective, they present "some very challenging issues."

The good news, he said, is that patients with migraine without aura aren't at any important risk for WMAs or ILLs, and prospective studies show no cognitive penalty for migraine or for these MRI changes.

"Physicians can thus continue with current practice recommendations that in patients with migraine and a normal examination, no imaging is required."

With regard to the evidence for infarct-like lesions, "given that they are no more common in migraine with or without aura than controls, it can be argued that migraine itself is no reason to image," said Dr. Goadsby. If there is a concern about cerebrovascular disease, "that should be dealt with on its own merits," he said.

As for volumetric changes, Dr. Goadsby agreed with the authors that this area remains an area of research. A major physiologic question is whether these changes are part of the migraine condition (eg, static and associated with the disorder) or whether they're a consequence (eg, progressive in some way with disorder activity). "For the moment, one could conclude the former," he said.

Because there is no cognitive or other "penalty" for migraines, and they seem static as far as has been tested (with the caveat that much more longitudinal data are needed), the findings may "simply mark the inheritance of migraine," said Dr. Goadsby.

"Resolving this question is hugely important and will require well-funded large-scale, population-based imaging as the outcome," he concluded.

The study was supported by the Lundbeck Foundation and the Novo Nordisk Foundation. Dr. Ashina received honoraria for lecturing from Allergan and Neorogesx and is a consultant for Depomed.

Neurology. 2013;81:1-9. Published online August 28, 2013. Abstract

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