Hypertension is historically recognized as the most important risk factors for lacunar infarcts (Fisher 1965). Other established risk factors include age, diabetes mellitus, ischemic heart disease, transient ischemic attacks, and cigarette smoking. Besides the absolute level of blood pressure, persistent nighttime hypertension, high pulse pressure, and abnormal circadian variation, such as a higher magnitude of nocturnal systolic and diastolic blood pressure dip (Castilla-Guerra et al 2009), may represent important risk factors. These risk factors may cause structural changes in small arteries with resulting loss of cerebrovascular autoregulation. In patients with Binswanger disease and multiple lacunes, significant impairment of cerebrovascular reactivity with cerebral blood flow reduction has been demonstrated by multiple methods such as Transcranial Doppler ultrasound (Molina 1999), SPECT scan (Ohtani 2003), and functional MRI (Hund-Georgiadis 2003). In the absence of a large vessel stenosis, an impaired cerebrovascular reactivity may reflect increased rigidity of the vascular wall; a negative correlation was found between the number of lacunar infarcts and cerebrovascular reactivity (Molina 1999). A lower basal cerebral blood flow velocity, higher pulsatility index, and a higher resistivity index have been also associated with small-vessel disease. The increased pulsatility index was the strongest independent predictor of microvascular disease (Chamorro 1997). In this situation, cerebral blood flow is not maintained when a drop in systolic blood pressure and diffuse incomplete ischemia of white matter or lacunar infarction may result (O’Sullivan 2002). An increased susceptibility to upright position followed by reduction of cerebral blood flow without significant changes of the systemic blood pressure has been also suggested (Ohtani 2003). Due to its current aggressive management, the role of hypertension in the genesis of lacunar infarction is probably less important than in the past.
Intracranial branch atheromatous disease causes a vasculopathy generically called “microatheroma," which is different than hypertension-induced lipohyalinosis. Severe carotid plaques give a greater than 10-fold increased risk for lacunar infarctions in the elderly (Hollander 2002). Even early stages of carotid stenosis (less than 60%) increase the risk for lacunar infarctions: each standard deviation in plaque score results in a 1.4-fold increased risk for lacunar infarction (Nagai 2003). Isolated carotid stenosis has been more frequently associated with multiple, homolateral lacunar infarctions, particularly when the stenosis is greater than or equal to 75%. Patients with dolichoectasia of intracranial vessels are 42% more likely to develop lacunar infarcts than patients without (17%). Another study also found an increased incidence of lacunar infarctions in patients with dolichoectasia (36%) versus control subjects (19%) (Pico 2003). There is an independent and poorly understood, pathologically demonstrated, association between intracranial dolichoectasia and small vessel disease/lacunar infarctions. Patients with dolichoectasia of intracranial vessels are more likely to develop lacunar infarcts than patients without, independent of age, diabetes, and hypertension (45% vs. 18%) (Pico 2007). Carotid artery intima-media thickness, determined by B-mode ultrasonographic measurements, was found significantly higher in nonlacunar versus lacunar strokes (Cupini 2002).
Diabetes mellitus is present in 2% to 37% of patients with lacunes, and lacunar infarctions are more common in diabetics than in nondiabetics (35.1% vs. 23.9%) (Arboix 2005). Excessive glycation and oxidation, endothelial dysfunction, increased platelet aggregation, and impaired fibrinolysis appear to underlie the pathogenesis of diabetes-related stroke. Insulin resistance was found to be an independent risk factor for lacunar and atherothrombotic infarctions. Left ventricular hypertrophy, electrocardiographic ST segment depression, and increased body mass index are also risk factors for lacunes (Fisher 1965).
Experimental studies support embolic pathogenesis of lacunes, and aortic arch atheroma may be associated with increased risk of lacunar strokes. In patients older than 85 years of age with lacunar infarcts, atrial fibrillation is more frequent than in patients younger than 85 (28.2% vs. 8.7%); it is possible that in this age group, cardioembolic pathogenesis of lacunes is more important than originally thought. A higher prevalence of thoracic aorta atherosclerosis has been found in patients with lacunar infarction (Saleem 2003). Microthrombi rather than atheroemboli can result in small areas of necrosis resembling lacunar infarcts primarily located in the striatum and thalamus (Rapp et al 2008).
Lipid and lipoprotein abnormalities have been implicated in the pathogenesis of cerebrovascular disease. Increased apolipoprotein B and apolipoprotein A are considered risk factors for lacunes. A Chinese study showed that an increased plasma level of lipoprotein(a) causes a 2.05-fold increased risk for lacunar infarction (Sun 2003). Serum saturated fatty acids may increase the risk for lacunes, whereas serum linoleic acid appears to be protective. In Japanese, a linear and independent association between plasma levels of homocysteine and lacunes was found. Homocysteine may be a stronger predictor for diffuse white matter disease than isolated lacune, acting via endothelial dysfunction (Hassan 2004).
Multiple genetic factors have been found to have a role in the pathogenesis of cerebrovascular disease. Particular genotypes of angiotensin-converting enzyme, angiotensinogen, and angiotensin II type 1 receptor were associated with increased risk for lacunes. The T-786C genotype of endothelial nitric oxide synthase potentiates the oxidative stress induced by smoking, The platelet glycoprotein Ib[alpha] genotypic variation and alpha-1-antichymotrypsine gene A1252G variant are considered genetic risk factors for lacunar infarction. The association of some IL-6 genotypes with lacunes suggests that lacunar stroke may result from a genetic susceptibility to inflammation superimposed on atherosclerotic risk factors.
Binswanger disease has a high association with lacunar infarction (40.3%) (Wiszniewska 2000) and CADASIL causes lacunar strokes in over 80% of cases. Recently, it has been found that the most important predictor of cognitive dysfunction in CADASIL is lacunar infarct lesion load visible on the MRI and not the microbleeds or white matter hyperintensities (Liem 2007). Three-dimensional MRI analysis of individual lacunar volume suggested that the most important determinants of lesional volume are genetic predisposition and anatomical factors, rather than vascular risk factors (Herve et al 2009). Other vascular diseases, such as dissection, vasculitis, drug abuse, and neurosyphilis may cause lacunar infarcts. Recently, it has been suggested that in periarteritis nodosa, a nonvasculitic, small artery, thrombotic microangiopathy gives rise to lacunar stroke syndromes early in the course of the disease.
Chronic kidney disease with poor glomerular filtration rate may associate glomerular and cerebral small vessel disease due to similarities of the 2 vascular beds (Ikram 2008). By causing endothelial dysfunction, chronic renal disease can independently increase the risk of lacunar infarcts even in individuals without hypertension or diabetes (Wada et al 2008a).