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Midlife Migraine Linked to Later Parkinson's
Medscape Medical News
September 17, 2014

Patients with midlife migraine, particularly migraine with aura, are more likely than those without headache to report parkinsonian symptoms and to be diagnosed with Parkinson's disease (PD) later in life, a new study suggests.

Further, women with migraine were more likely to have a parent or sibling with PD, and headache was also associated with restless legs syndrome, another movement disorder.

"Our finding linking migraine with different indicators of parkinsonism suggests shared cerebral vulnerability that could reflect common pathology, genetic or environmental risk factors, or changes in the brain from one condition that increases the likelihood of symptoms reflecting the other conditions," the researchers, with lead author Ann Scher, PhD, professor, epidemiology, Department of Preventive Medicine and Biometrics, Uniformed Services University, Bethesda, Maryland, and the National Institute on Aging, conclude.

"Future longitudinal studies with more targeted brain imaging and neurologic examinations are warranted," they add.

The study is published online September 17 in Neurology.

Headache Classifications
Migraine is the most common brain disorder in both men and women, affecting 6% to 7% of men and 17% to 18% of women in the general population. Of those who get migraine, about 25% to a third have accompanying auras, said Dr. Scher.

Researchers used data from the Reykjavik (Iceland) Study (RS), a population-based cohort study established in 1967 that included a random sample of men and women born between 1907 and 1935. At a mean age of 51 years, participants were asked about headache symptoms. Those reporting headaches at least once a month were asked about accompanying symptoms, such as nausea, vomiting, and photophobia.

Patients were classified into 4 groups: no headache (n = 3924), nonmigraine headache (n = 1028), migraine without aura (n = 238), and migraine with aura (MA; n = 430).

Researchers also used the follow-up Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik Study), which examined 5764 RS survivors from 2002 to 2006. During interviews conducted at a mean age of 77 years, participants were asked about 6 motor function suggestive of parkinsonism.

About 8.9% of the patients reported 4 or more such parkinsonism symptoms. Such symptoms were more common in those with midlife headache than controls, particularly for MA (adjusted odds ratio [OR], 3.61; 95% confidence interval [CI], 2.7 - 4.8). Those with migraine with no aura had 2.27 times the odds of these symptoms.

The results were similar after exclusion of patients with a current prescription for a dopamine antagonist.

About 1.2% of patients reported receiving a diagnosis of PD. Those with migraine with aura were more likely than controls to have this diagnosis (adjusted OR, 2.53; 95% CI 1.2 - 5.2).

About 6.6% of patients reported having at least 1 parent or sibling with PD. Women, but not men, with midlife MA were more likely to have a family history of PD than controls, which Dr. Scher called "an intriguing finding," although it's not clear what it means.

As well, migraineurs were more likely to have restless legs syndrome, also known as Willis-Ekbom disease. This condition was more common among patients with all types of headache, not just MA (OR, 1.45), than among controls without headaches, with results being similar among men and women.

All 6 individual parkinsonism symptoms were more common in patients with midlife MA compared with controls. The strongest association was for tremor (OR, 2.90; 95% CI, 2.2 - 3.8) followed by arm rigidity (OR, 2.60; 95% CI, 2.0 - 3.3).

Researchers found significant but small group differences in median walking time using the 6-meter walking test. Compared with controls, patients with midlife headache were more likely to be in the slowest 10% of patients, although Dr. Scher said she doesn't think this is clinically significant because of the large sample size.

Driving Factors
Several factors could be driving the association between midlife migraine and later PD, including cerebrovascular disease. But Dr. Scher feels it's unlikely that this is the most important underlying cause because the study controlled for related risk factors, including infarct-like and white matter lesion load on brain MRI.

"I think we can rule that out in this study population, given that we accounted for this in a very robust way," she told Medscape Medical News.

She also doesn't think the connection between migraine and PD can be explained solely by dopamine dysfunction, which is related to PD and has been linked to migraine, because the study also looked at this factor.

Perhaps a more likely mechanism is head injury. "Headache is a common symptom following a head injury and head injury has also been linked to parkinsonism," said Dr. Scher. She also noted that in this study, both men and women with migraine with aura were about twice as likely as controls to report a history of a moderate to severe head injury.

"It's an interesting finding, but we can't really make much more of it because we don't know when these head injuries occurred," she said. "But it indirectly supports that it might be a possible link."

Dr. Scher speculated that another potential culprit might be iron deposition. Some studies have shown iron deposition in the basal ganglia in people with PD, and a few small studies have shown that migraineurs are more likely to have iron deposition, she said.

"It's not clear what this iron deposition means, whether the iron itself is harming the brain or if the iron is somehow a marker for some other process."

The connection between migraine and PD may involve more than 1 route, too, added Dr. Scher. "It's not necessarily mutually exclusive; for example, some studies have suggested that dopamine pathways may be involved in recovery from head injury, so it could be some sort of a genetic/environmental interaction."

Dr. Scher is doing research assessing headaches in a recently deployed military population. "If what we are seeing in this older cohort in Reykjavik, Iceland, is somehow related to head injury, then that's going to inform some of the ways in which we analyze the data in this young military cohort."

She also wants to study an older military cohort that is approaching the age where they might start getting parkinsonism symptoms to see whether there are any links with migraine.

Intriguing" Results
Reached for a comment, Michael S. Okun, MD, professor, University of Florida Health, Gainesville, Florida, and national medical director, National Parkinson Foundation, said he found the study results "intriguing" but stressed the need for verification.

"This is an association study, so I would caution anyone about trying to make conclusions," said Dr. Okun, adding that such studies tend to "cast a wide net."

"If you run enough statistical tests, you'll find associations and that's okay; there's nothing wrong with that," Dr. Okun told Medscape Medical News. "But that's why you need to replicate these studies and you need to be as methodologically controlled as you can be. The authors did their best with the cohort they had, but now they have to sit back and see if other investigators can replicate it."

People should remember that migraine is very common before "making the jump" to a causal link between these 2 conditions, he said.

He also noted that it's difficult to firmly establish whether the migraine patients in the study actually had PD. "It's almost impossible to do that in a longitudinal study like this," he said. "There could be diagnostic uncertainty of what the cases actually were; things like head trauma and strokes and other things can results in symptoms that look like PD."

The AGES-Reykjavik Study was supported by a grant from the National Institutes of Health, the National Institute on Aging Intramural Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Dr. Scher serves on a scientific advisory board for Allergan Inc and is an associate editor for Cephalalgia and Pain Medicine. Dr. Okun reports he receives no industry honoraria.

Neurology. 2014;83:1246-1252 Abstract
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