Small Brain Lesions Equal Big Stroke, Big Mortality Risk

Very small (<3 mm) brain lesions, which are often dismissed as benign, more than triple the risk for stroke and stroke-related death in asymptomatic middle-aged and older adults with no history of clinical stroke, new research shows.

As well, the study showed that having larger lesions (3 mm or greater) also increases the risk for stroke and that having both sizes of lesion raises the stroke risk by almost 9-fold.

While the results suggest that very small lesions are clinically important, this new information is just one step toward changing clinical practice, according to lead author B. Gwen Windham, MD, MHS, associate professor, medicine, University of Mississippi Medical Center in Jackson.

“To move clinical practice forward, we have to move the science forward first. This new study has enlightened us to the potential of an early marker of disease and pathology, and maybe we could use that to change practice down the road.”

The study was published online July 6 in Annals of Internal Medicine.

Increased Stroke Risk, All-Cause Mortality

The Atherosclerosis Risk in Communities study included 1884 adults aged at least 55 years (mean age, 63 years) from two communities — Forsyth County, North Carolina, and Jackson, Mississippi — who underwent MRI. Half of the participants were black and 60% were women.

Researchers defined subclinical brain infarctions by shape, absence of mass effect, and hyperintensity to gray matter on proton density-weighted and T2-weighted images. They defined lacunes as 3- to 20-mm noncortical lesions in the basal ganglia, brainstem, thalamus, internal capsule, or cerebral white matter. Nonlacunar lesions were 3- to 20-mm lesions outside these areas or lesions larger than 20 mm in any area on right-to-left or anterior-to-posterior measurements.

Investigators detected clinical strokes requiring hospitalization through yearly telephone interviews and surveillance methods that included hospital record reviews and medical chart abstraction. They identified deaths through contact with next of kin, hospital records, state death records, and the National Death Index.

Over an average follow-up of 14.5 years, there were 157 clinical strokes, 50 stroke-related deaths, and 576 all-cause deaths. Lesion size (<3 mm only, ≥3 mm only, or both) was associated with typical cerebrovascular disease risk factors, including older age, black race, lower education, smoking, diabetes, hypertension, antihypertensive medication, systolic and diastolic blood pressure, and alcohol use.

After adjustment for potential confounders, such as age, sex, race, diabetes, and hypertension, the presence of lesions smaller than 3 mm was associated with a 3-fold increased risk for incident stroke (hazard ratio [HR], 3.47; 95% confidence interval [CI], 1.86 – 6.49) compared with no lesions.

The presence of lesions 3 mm or larger was associated with almost a 2-fold increased risk (HR, 1.94; 95% CI, 1.22 – 3.07). The HR for having both sizes of lesion was 8.59 (95% CI, 4.69 – 15.73).

Having the smaller lesions was associated with a 3-fold increased risk for stroke-related death (HR, 3.05; 95% CI, 104 – 8.94) but not all-cause death. Conversely, having larger lesions was associated with an almost 2-fold increased risk for all-case death (HR, 1.90; 95% CI, 1.48 – 2.44), but was not statistically associated with risk for stroke-related death.

The presence of lesions of both sizes increased the risk for both stroke- related death and all-cause death.

The bigger risk with smaller lesions could be explained by the involvement of a different type of pathologic abnormality compared with larger lesions, said Dr Windham. She also pointed out that there were relatively few smaller lesions and that the CIs for the smaller lesions overlapped with those for the larger lesions.

The number of lesions also played a role in stroke risk, regardless of lesion type. This, said Dr Windham, supports a “dose-response” mechanism.

Small Lesions Often Dismissed

Radiologists tend to dismiss very small lesions. The thinking, said Dr Windham, is that these represent clinically nonsignificant lesions or even benign spaces around a blood vessel (perivascular spaces) instead of actual pathologic lesions. This is especially true with use of older MRI, for which the pixel resolution is relatively low.

But the new study shows that this thinking may be misplaced. “What this study shows is that even these very small abnormalities that we would normally ignore are associated with this increased risk of stroke and death,” said Dr Windham.

“If participants in the study had the small lesions, there was increased risk, but if they had the small ones plus the ones that we are already recognizing as risky, then that risk appeared to be even higher.”

The study also showed that white matter hyperintensities were associated with a higher risk for stroke and death.

“That was supportive and in line with what has been reported in older populations,” said Dr Windham.

“We think part of the pathology there also relates to vascular disease, but newer science indicates it may be more than just ischemic vascular disease; there may be other things in the vasculature — things apart from hypertension or diabetes — that may aggravate pathological changes in the vascular system,” she added.

Having 1 or more lacunes also increased the risk for stroke compared with no lacunes, which wasn’t surprising to Dr Windham. The analysis replicated findings from other studies, she said.

In terms of predictors, hypertension had the most robust association with very small lesions (relative risk ratio [RRR], 2.17; 95% CI, 1.14 – 4.13; P = .018) followed by age (RRR, 1.07; 95% CI, 1.00 – 1.14; P = .051), and black race (RRR, 1.79; 95% CI, 0.91 – 3.51; P = .092).

Having larger lesions only was associated with hypertension as well as older age, black race, and current smoking status. Older age, black race, smoking, and hypertension were associated with lesions of both sizes whereas higher education was protective.

The relationships uncovered in the study were similar in white and black patients.

Because the study findings won’t change clinical practice right away, clinicians should continue to advise patients to control hypertension and diabetes, not to smoke, and to minimize other cardiovascular risk factors, said Dr Windham. She does not recommend routine MRI to detect very small brain lesions.

Call to Action

Commenting on the findings for Medscape Medical News, Ralph Sacco, MD, professor and chair, Department of Neurology, University of Miami Miller School of Medicine, Florida, and past president, American Heart/American Stroke Association, agreed that it’s inappropriate to use MRI for all patients, partly because of the expense.

He said the study is “another call to action” for neurologists and primary care doctors to help their patients control vascular risks. “When physicians who are taking care of a patient get an MRI report back that was done for another reason (that indicates the presence of very small lesions), they may want to take these findings more seriously and be a little more aggressive in risk factor management.”

Dr Sacco said he found the study “interesting” and “well done” in that it included a relatively long follow-up and large cohort and it focused on middle-age to older patients. “It still found a predictive value to these lesions in people who are even younger than those in usual studies.”

In addition to stroke and mortality, brain lesions may be associated with other outcomes, including cognitive changes, dementia, and mobility. According to Dr Sacco, such outcomes could be the subject of future studies.

The authors report grants from the National Heart, Lung, and Blood Institute and TauRx Therapeutics during the conduct of the study and personal fees from Lundbeck, the Dominantly Inherited Alzheimer Network, and the American Academy of Neurology outside the submitted work. The authors and Dr Sacco have disclosed no relevant financial relationships.

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