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Brain Lesions Associated with Migraine May Not Be Clinically Relevant

Fitzgerald, Susan

doi: 10.1097/01.NT.0000426343.00513.81
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Investigators reported that small white matter hyperintensities in most patients with migraine were not associated with a risk for cognitive decline.

The brain lesions found on MRI scans of migraine patients are probably not a cause for alarm, according to a nine-year follow-up study.

It's been a worry that the deep white matter hyperintensities typical for migraine might mean that patients are at risk for experiencing cognitive decline. But that turned out not to be the case when a team of researchers from the Netherlands did MRI brain scans and cognitive testing on migraine patients and a group of controls in 2000 and then repeated the assessments in 2009.

“The results of this longitudinal study are reassuring to patients and their physicians on several levels,” noted the authors of an editorial that accompanied the study in the Nov. 14 edition of the Journal of the American Medical Association (JAMA). “The findings imply that small white matter hyperintensities in most patients with migraine should not be a reason for alarm,” Deborah I. Friedman, MD, MPH, professor of neurology and ophthalmology at the University of Texas Southwestern Medical Center, and David W. Dodick, MD, professor of neurology at the Mayo Clinic in Scottsdale, AZ, wrote.

The JAMA study is a follow-up to the Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis (CAMERA-1) study, which found a higher prevalence and greater volume of MRI-measured deep white matter hyperintensities, infratentorial hyperintensities, and posterior circulation territory infarct-like lesions in migraine patients compared with a control group, according to the JAMA report. Such lesions are believed to be of ischemic origin, and white matter hyperintensities in particular have been associated with increased risk of ischemic stroke and cognitive decline, the JAMA report noted. But whether the lesions are clinically relevant in the case of migraine is a matter of debate.

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The CAMERA-1 study included 295 migraine patients and 140 controls matched for age and sex. They were given MRI scans and other assessments in 2000 and invited to return for evaluation in 2009. The follow-up response was very good — 203 of the original migraine patients and 83 of the controls underwent the second MRI. The average age of participants in the migraine group at follow-up was 57 and 77 percent were women. The average age for controls was 55, and 69 percent were women.

In addition to an MRI, the follow-up evaluation included a structured computer-guided telephone interview, physical examination, and cognitive testing similar to the original protocol. Participants were questioned about previous, current, and newly developed migraine attacks. The questionnaires used personal benchmarks (such as pregnancy) to help participants determine when their migraine attacks began and ended. To ensure that technological differences did not influence results, the researchers used the same MRI scanners and protocols from the original study.

The primary outcome measure for the follow-up study was change in the number and volume of MRI-measured deep white matter hyperintensities in migraine patients versus controls. Progression of posterior circulation territory infarct-like lesions and infratentorial hyperintensities were also evaluated. The researchers analyzed whether the progression of lesions was associated with the patient's reported history of migraine activity and whether more lesions were associated with cognitive decline.



Among their findings, the research team reported that among men, there was no association between migraine and progression of MRI-measured brain lesions, but among women, 77 percent of those in the migraine group and 60 percent in the control group had a progression of deep white matter hyperintensities. The incidence of progression was highest among women without aura.

The investigators defined progression as a greater than 0.01 ml increase in volume of total lesion load. Although these female migraine patients had a higher number of new lesions compared with women without migraine, the total volume of lesions was not associated with a negative cognitive effect, Mark C. Kruit, MD, PhD, a study coauthor who is a neuroradiologist at Leiden University Medical Center in the Netherlands, told Neurology Today in an e-mail.

There was also no significant association of migraine with progression of infratentorial hyperintensities or new posterior circulation territory infarct-like lesions.

The researchers also found no association between the number or frequency of migraine headaches with progression of lesions, and there were no significant differences in cognitive functioning between the migraine group and the controls at follow-up. Deep white matter hyperintensity load was not associated with cognitive performance.

“There still remains the question of what causes the lesions and why it is cumulative when people stopped having migraine attacks,” Dr. Kruit said. “Whether lesions may further accumulate and then have a later effect on cognitive function can't be excluded [from consideration], but then also the effects are not expected to have a clinical impact.

“Doctors should just go on treating migraine patients as they are used to doing,” Dr. Kruit continued. Although larger volumes of white matter lesions have been correlated with a decline in cognitive ability, in the case of migraine “the amount of lesions is relatively low, and these amounts of lesions do not have evident functional correlates.”

The study authors noted that clinicians sometimes struggle with how and to what extent to explain the meaning of white matter lesions to their migraine patients. The brain lesions are typically noted in the radiology report, but what impact they have on the patient's course of disease and treatment plan is a different issue.

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Sheena Aurora, MD, associate professor of neurology at Stanford University, who was not involved with the study, told Neurology Today that “most patients want to know what these lesions mean. Does it mean they are going to cause memory problems? Does it mean they are going to increase their risk of dementia or stroke?”

Dr. Aurora said the latest study results will allow her to offer reassurance to those patients who worry about the long-term implications of migraine-related lesions.

Randolph Evans, MD, a Houston neurologist and clinical faculty member at Baylor College of Medicine, agreed that “this study should be reassuring to patients that the lesions are relatively benign.”

Still, many questions remain. “The major thing we don't know is what causes these white matter abnormalities” in migraine, Dr Evans said. Although white matter lesions are thought to be due to gliosis, “you can't say these are little strokes as there is no definite evidence that the lesions are due to ischemia,” he pointed out.

Dr. Evans said some clinicians see value in putting migraine patients without risk factors on aspirin as a preventative therapy against stroke, but he questions the benefit. “Daily aspirin has a small risk of bleeding complications with no benefit demonstrated to date in this population.”

Dr. Kruit noted that the new study was not designed to focus on the question of risk of future stroke.

Joel Saper, MD, clinical professor of neurology at Michigan State University and director of the Michigan Head Pain & Neurological Institute in Ann Arbor, said that as a clinician he has felt compelled to talk to patients about the presence of lesions on their MRI, “and that, of course, created a lot of anxiety.”



“Now we can say the spots themselves don't seem to be a marker for risk, but that doesn't mean we don't try to control risk factors” for both migraine attacks and cardiovascular disease, he told Neurology Today.

The JAMA editorial noted that, “given the relationship between migraine and several acquired and genetic vasculopathologies, it is possible that certain subpopulations of patients with migraine may be at increased genetic risk for significant white matter disease and neurological morbidity, including stroke, transient ischemic attack, cognitive impairment, and other neurologic outcomes.”

“Addressing modifiable risk factors for stroke — such as obesity, smoking, hypertension, hypercholesterolemia, and physical inactivity — and avoiding high-dose combined oral contraceptive in women older than 35 years and in those with untreated or poorly controlled vascular risk factors seems prudent,” they wrote.

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• Palm-Meinders IH, Koppen H, Kruit MC, et al. Structural changes in migraine. JAMA 2012; 308(18):1889–1897.
    • Freidman DI, Dodick DW. Editorial: White matter hyperintensities in migraine: Reason for optimism. JAMA 2012; 308(18): 1920–1921.
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