Traumatic Brain Injury Linked to Increased Stroke Risk

Pauline Anderson

June 27, 2013

A new study has shown a strong association between traumatic brain injury (TBI) and later development of ischemic stroke that remained significant even after adjustment for several potential confounders, such as vascular risk factors and comorbid conditions.

The association was similar in magnitude to that of hypertension, which is the leading stroke risk factor, but lead author James F. Burke, MD, Department of Veterans Affairs (VA), VA Center for Clinical Management and Research, Ann Arbor VA Healthcare System, VA Center for Clinical Management and Research, Ann Arbor VA Healthcare System, and Stroke Program, University of Michigan, Ann Arbor, is not yet prepared to call TBI a stroke risk factor.

"I would say this is a striking and surprising finding, but I don't think we're at the point yet where we would remotely characterize this as saying we have another risk factor for stroke," he said.

The study was published online June 26 in Neurology.

Persistent Association

The retrospective cohort study included 1,173,353 patients who visited the emergency department or were hospitalized for a traumatic or nontraumatic brain injury in California from 2005 to 2009. Of these, 37% had a TBI.

During a median follow-up of 28 months, there were 11,229 ischemic strokes: 1.1% in the TBI group and 0.9% in the non-TBI trauma group.

After adjustment for demographic characteristics, vascular risk factors, comorbid conditions, trauma severity, and trauma mechanism, TBI was robustly associated with ischemic stroke (hazard ratio [HR], 1.31; 95% confidence interval, 1.25 - 1.36). The association was changed only slightly when covariates were serially added: demographic characteristics: HR, 1.34; addition of vascular risk factors: HR, 1.30; addition of comorbid conditions: HR, 1.30; and addition of injury severity and trauma mechanism: HR, 1.31.

All TBI subtypes had a similar magnitude of association with ischemic stroke, which was lessened only modestly when stroke hospitalizations within 7, 30, 60, or 365 days of the trauma were excluded.

The magnitude of the association was greater among younger patients (odds ratio [OR],1.56 for those under age 50 years, vs 1.22 for those 50 years and older).

"The surprising thing was that we took away potential confounders systematically, one at a time, and the association persisted, and strongly so, no matter how we tried to explain it," said Dr. Burke.

"This is stronger data than I thought it was going to be when we started, given the robustness of the association and the fact that it held up over a wide variety of circumstances controlling for a lot of things that we could credibly control for," he added.

The associations uncovered by this study were similar to those found in an earlier Taiwanese study, but that research did not "have much in the way of controlling for confounding," said Dr. Burke.

Vascular Theory

The current study does not make clear how TBI might raise stroke risk, but there are several theories, one of which involves accrual of vascular risk factors, something this study was unable to control for, said Dr. Burke.

"It may be the case that personality changes associated with TBI result in changes in cognition that may lead to behavior changes that put you at risk down the road. So it may be that patients with TBI accrue hypertension, accrue hyperlipidemia, accrue diabetes, at a greater rate than do patients who do not have TBI."

Dr. Burke believes that the differential accrual of vascular risk factors probably matters more in the younger age group, where the association of TBI with ischemic stroke seems so strong. "Young people have a very low absolute risk for stroke and if they acquire vascular risk factors at a greater rate, that's going to look like a greater effect relative to the population where vascular factors are already substantially more prevalent."

The association in the younger age group, added Dr. Burke, may be "one of the threads" tying the research together. "It's an important part, because it really does say that the group we're most interested in — where the association is most important — is also where it's strongest."

Another theory is that the association is through vascular dissection, a well-known stroke mechanism that has already been linked to TBI. Although the study excluded dissection-mediated strokes, some dissections were probably not coded or categorized because they are not something that doctors routinely look for.

"We do lots of noninvasive vascular imaging, and at least anecdotally we run across dissections," said Dr. Burke. "This may be a more prevalent phenomenon than we realize, and it may be something that creates a greater degree of risk over time than we understood."

Dr. Burke is interested in assessments of a larger population with TBI, perhaps using a different study design. The armed forces may be a good place for such a study, he said. The military has been very interested in TBI, but to date the research has focused on outcomes known to be problematic, such as cognitive and behavioral outcomes and mood disorders.

Role for Migraine?

Asked for his view of the study, David W. Dodick, MD, professor, Department of Neurology, director, headache program, Division of Cerebrovascular Neurology, Mayo Clinic, Phoenix, Arizona, and member of the American Academy of Neurology, said the authors certainly raise the possibility that TBI is an independent risk factor for ischemic stroke, even well beyond — more than 60 days — the immediate postinjury phase.

But, as the authors suggest, this needs to be confirmed in longitudinal prospective studies that control for all potential confounders, including, for example, use of tobacco and oral contraceptives, both of which may increase the risk for ischemic stroke in women, particularly in those with migraine, said Dr. Dodick.

He also noted the absence of migraine in the study. The lifetime risk for migraine in women is over 30%, and the Women's Health Study recently showed that migraine with aura is a more potent risk factor for ischemic stroke than are even hypertension and diabetes mellitus, said Dr. Dodick.

"While the authors acknowledged the potential for misdiagnosis of seizure as a stroke, it is more likely in a clinical setting that migraine with aura, which is common after TBI, is more often a challenge for clinicians to distinguish from TIA [transient ischemic attack] or stroke and more closely resembles stroke than does epilepsy."

The study results probably won't alter clinical practice, added Dr. Dodick. "Since this is a preliminary and retrospective study that does not confirm a causal association, and because the absolute risk appears to be very small, this study does not immediately impact the clinical standards of care for such patients nor justify specific stroke prevention measures, other than, of course, usual modification for established stroke risk factors such as hypertension, dyslipidemia, etc."

The study was supported by an advanced fellowship through the Department of Veterans Affairs. Dr. Burke is supported by that fellowship.

Neurology. 2013;81:33-39. Published online June 26, 2013. Abstract

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