Keeping an Eye on Lacunar Infarction
- brain infarction
- cerebral infarct
- cerebrovascular accident
- cerebrovascular disease
- lacunar infarcts
- optical imaging
- retinal ischemia
See related article, pages 1349–1355.
Mild hypertensive retinopathy independently predicts lacunar infarction, according to a report in this issue of Stroke from the ever-bountiful Atherosclerosis in Communities (ARIC) prospective cohort study.1 It is important news, giving us a new way to explore a poorly understood infarct subtype. Although some might still wonder whether we haven’t known for decades that hypertension leads to lacunar infarction, the story is not so simple. Careful meta-analysis of case-control studies evaluating risk factors for infarct subtypes found only a slightly higher prevalence of hypertension in lacunar compared with nonlacunar infarct cases.2 The observation raises the question: Why do some people with high blood pressure suffer lacunes when others do not? The causal pathway is probably complex, and it bears noting that when C. Miller Fisher connected hypertension to lacunar infarction in 1953, he took pains to clarify that “… hypertension itself does not lead to closure of cerebral vessels ….”3
It makes sense to look at retinal vessels to try to tease out what is happening to cerebral vessels. The retina derives embryologically from the diencephalon and has similar vascular characteristics, including nonneurogenic autoregulation of blood pressure, as well as a blood-ocular barrier built of specialized endothelial cells supported by astrocytes and pericytes.4 Looking at the eye for clues about stroke is not a new idea: pathological correlations between the retinal artery and cerebrovascular disease date back 70 years at least.5 However, retinal artery photography has dramatically improved the task of identifying retinal vascular pathology in vivo, offering standardization, quantification, and interrater reliability far beyond what is possible for a clinician wielding an ophthalmoscope.4 Although retinal imaging plays no role in the routine management of hypertension, it is a tremendous boon for research.
Prior studies from the ARIC investigators have used retinal artery imaging to establish relations between retinal artery pathology and incident stroke,6 periventricular leukoaraiosis,7 and subclinical infarction.8 More recently, cross-sectional studies that included the use of retinal photography compared lacunar infarction with nonlacunar stroke types and associated retinal microvascular changes with lacunar infarction9,10 and deep intracerebral hemorrhage.10 Now the ARIC investigators have taken this line of research a step further, establishing for the first time a clear link between retinal artery injury and incident lacunar infarction in a rigorously conducted, prospective cohort study.
Signs of “hypertensive retinopathy” may be classified according to their associations with end-organ disease, according to a recently proposed scheme.11 The “mild” category might be described as retinal microvascular signs: focal or generalized arterial narrowing, arteriovenous nicking, or opacity (“copper wiring”) due to thickening of the arteriolar wall. The “moderate” category includes more severe vasculopathy or damage to the retina itself: microaneurysms, hemorrhages, hard exudates, or cotton-wool spots caused by retinal ischemia. The “malignant” category includes any mild or moderate signs plus swelling of the optic disk and is an indication for urgent blood pressure reduction. The term “hypertensive retinopathy,” though commonly used, is an overdetermined misnomer, as “mild” microvascular signs may be seen in people >40 of age without hypertension,12 whereas “moderate” retinopathy signs are common in diabetics without hypertension.
ARIC obtained interpretable retinal photographs for >10 000 stroke-free subjects and identified signs of microvascular injury and retinopathy without regard to hypertension. The outcome for this study was hospitalized ischemic stroke, of which there were 332 cases during a median follow-up of 11 years. Infarcts were divided into 66 lacunar (unmeasured or <2 cm infarction in an appropriate territory), 80 cardioembolic, and 192 nonlacunar thrombotic infarcts. After multivariate adjustment including use of antihypertensive medication, systolic blood pressure, and diabetes, lacunar infarcts but not other infarct subtypes were uniquely associated with each of the “mild” retinal microvascular signs. “Moderate” retinopathy signs were not associated independently with lacunar infarction but were associated with cardioembolic and nonlacunar thrombotic subtypes. The finding is interesting and bears further exploration because it demonstrates that not all “hypertensive retinopathy” is created equal in relation to cerebrovascular pathology.
So how do we apply these new findings? Retinal photography does not offer clinical value as a screening tool for stroke risk because retinal microvascular signs are common, turning up in 2% to 15% of adults,12 whereas lacunar infarction is less common. Even among people with severe arteriolar narrowing, the risk of lacunar infarction was <0.1% per year in this study. With an event rate that low, even clinical trials that use retinal microvascular signs as a surrogate outcome would not have credibility for prevention of lacunar infarction.
Instead, the study offers a way to explore risk factors that might be shared between retinal microvascular injury and lacunar infarction. For example, it is easy to imagine using retinal photography to enroll large numbers of subjects in studies seeking genetic determinants of vulnerability to retinal microvascular injury. That kind of approach is appealing because it is easier, faster, and cheaper to obtain a retinal photograph in an outpatient office than it is to obtain magnetic resonance imaging data. This article lends hope that in turn, the same genetic variations might be associated eventually with lacunar infarction as well. Then we finally might start to understand why some people suffer lacunes while most of us never do.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Yatsuya H, Folsom AR, Wong TY, Klein R, Klein BEK, Sharrett RA. Retinal microvascular abnormalities and risk of lacunar stroke: Atherosclerosis Risk in Communities Study. Stroke. 2010; 41: 1349–1355.
Jackson C, Sudlow C. Are lacunar strokes really different? a systematic review of differences in risk factor profiles between lacunar and nonlacunar infarcts. Stroke. 2005; 36: 891–901.
Rintelen F. Vergleichende pathologisch-anatomische Untersuchungen iiber das Verhalten der Netzhaut-, Gehirn-, Herz- und Nierenarterien. Schweiz Med Wschr. 1939; 29: 662–664.
Cooper LS, Wong TY, Klein R, Sharrett AR, Bryan RN, Hubbard LD, Couper DJ, Heiss G, Sorlie PD. Retinal microvascular abnormalities and MRI-defined subclinical cerebral infarction: the Atherosclerosis Risk in Communities Study. Stroke. 2006; 37: 82–86.
Baker ML, Hand PJ, Liew G, Wong TY, Rochtchina E, Mitchell P, Lindley RI, Hankey GJ, Wang JJ. Multi-Centre Retinal Stroke Study Group. Retinal microvascular signs may provide clues to the underlying vasculopathy in patients with deep intracerebral hemorrhage. Stroke. 2010; 41: 618–623.