STOWE, VT—Difficulty of migraine diagnosis and treatment may lie, in part, in the limited comprehension of the many complicating factors. At the Headache Cooperative of New England’s 17th Annual Head­ache Symposium, Marcelo Bigal, MD, PhD, attempted to navigate the wealth of information concerning white matter lesions, proposing a theory on how those lesions may develop.

There are a great number of conditions comorbid with migraine. Patent foramen ovale and high cholesterol, for example, are more common in individuals with migraine with aura, in which the migraine attacks are preceded by visual symptoms such as blurred vision, said Dr. Bigal, who is an Assistant Professor of Neurology at the Albert Einstein College of Medicine in Bronx, New York. Other conditions, such as depression, are more common in all forms of migraine. His own 2006 study demonstrated that obesity influenced the frequency of migraine occurrence. His study found that only 4.4% of migraineurs with normal weight experienced migraines frequently (10 to 14 days per month), compared with 5.8% of those who were overweight, 13% of those who were obese, and 20% of those who were morbidly obese.

Dr. Bigal drew a correlation between high cholesterol, obesity, and another recent finding—a genetic polymorphism that predisposes patients to high levels of homocysteine in the blood—that is more frequently seen in migraineurs. “All these situations may cause small vessel disease,” he said, which is radiologically manifested as leukoaraiosis, or changes in the white matter of the brain. “By definition, leukoaraiosis is a disease of the small vessels, not major arteries,” Dr. Bigal reasoned. “It’s not a cortical disease; it’s a deep brain disease happening around the small vessels.”

Consistently, Dr. Bigal said, research has proved that white matter hyperintensities are the result of chronic small vessel ischemia. A study by Sachdev et al from January 2007 found that hyperintensities, especially those in the deep white matter and the anterior brain regions, progress as people age—as much as 13.2% per year—and progression accelerates as the changes accumulate. However, debate still surrounds the impact of the accumulation on migraine.

“I would say that until three or four years ago, if you had MRIs from radiologists and the MRIs had white matter lesions, the radiologist would question if these were migraine lesions,” said Dr. Bigal. But a meta-analysis conducted by Swartz and Kern in 2004 appeared to put that argument to rest: With an odds ratio of 3.9, migraineurs were at an increased risk for white matter abnormalities, with or without comorbidity, regardless of age. Another study, this one by Kruit and colleagues and published in JAMA in the same year, further solidified the notion of white matter hyperintensities as a risk factor for migraine. In a general population sample, overall infarcts as diagnosed by MRI were comparable between 295 adult migraineurs and 140 controls; odds ratios were 7.6 for migraineurs and 13.7 for migraineurs with aura for posterior circulation infarct, when compared with controls. “The prevalence of white matter lesions increases as a function of the frequency of headache attacks,” further reported Dr. Bigal. “The higher the frequency of headache attacks, the more white matter lesions migraineurs had. This was true after one headache attack per month.”

Secreted inflammatory mediators are key components for the increased risk of white matter lesions, said Dr. Bigal. “[In the case of obesity,] the fat cells will secrete a bunch of inflammatory mediators and really increase the brain’s predisposition to migraine attacks.” The damage, however, only happens once the mediators can cross the blood-brain barrier.

According to Dr. Bigal, “The biological predisposition to migraine attacks is manifested in the form of cortical spreading depression activity. Cortical spreading depression is a wave of self-propagating depolarization” that is associated with changes in gene expression, which alters the action of a group of proteins called matrix metalloproteinases (MMPs). In addition to neuronal development and plasticity, MMPs are involved in opening the blood-brain barrier. Studies proposed that their affectation allows an influx of immune cells to the brain during cortical spreading depression.

An experiment by Gursoy-Ozdemir and colleagues, performed in 2004, is a fine example of this phenomenon, he said. In participants with induced cortical spreading depression, a huge activation of MMPs was observed, followed by an inflammatory invasion. “And these inflammatory cells have a predilection to the surroundings of the small vessels.” Sham-right and sham-left portions of the study confirmed that the changes failed to occur without induction of cortical spreading depression.

Dr. Bigal acknowledged that his theory is a leap from simple radiologic findings to a full-blown mechanism. “We can speculate that cortical spreading depression happening over time with this opening of the blood-brain barrier over time and inflammation over time will eventually cause chronic inflammation in the small vessels with white matter lesions and structural changes in the brain,” he said. “If that is true, drugs with high potential for inhibiting cortical spreading depression in animal models should prevent migraine pain and also the consequences of white matter pain.”

NR