Trends in Incidence, Risk Factors, and Survival in Symptomatic Lacunar Stroke in Dijon, France, From 1989 to 2006
A Population-Based Study
Background and Purpose— Lacunar infarcts are usually regarded as benign stroke, but population-based studies are required to assess the exact place of this stroke subtype in cerebrovascular pathology.
Methods— We evaluated trends in incidence rates, risk factor profiles, and survival rates in symptomatic lacunar stroke from a prospective population-based registry from 1989 to 2006.
Results— We recorded 2536 ischemic strokes. Among these, 715 (28%) were lacunar infarcts (354 men and 361 women). From 1989 to 2006, we observed a significant rise in the incidence of lacunar stroke in the 2 sexes considered together (relative risk, 1.02; 95% CI, 1.005 to 1.035; P=0.007), whereas the variation was not significant in either men or women when considered separately. Incidence rates significantly increased in young patients under 65 years old (relative risk, 1.049; 95% CI, 1.0175 to 1.0817; P=0.002). Concerning the distribution of cerebrovascular risk factors, lacunar stroke differed from nonlacunar stroke only with regard to the lower prevalence of a history of atrial fibrillation in the former (P<0.001). For lacunar infarcts, survival rates were 96% at 1 month (95% CI, 0.94 to 0.97), 86% at 1 year (95% CI, 0.83 to 0.89), and 78% at 2 years (95% CI, 0.75 to 0.81) and were significantly higher than those for nonlacunar stroke (hazard ratio, 2.05; 95% CI, 1.70 to 2.47; P<0.001).
Conclusion— Our results suggest a significant increase in the incidence rates of lacunar stroke with a relatively good short-term prognosis in terms of survival. The association among hypertension, diabetes mellitus, and lacunar stroke was no stronger than the association between these 2 risk factors and nonlacunar stroke.
Lacunar stroke, defined as small (<15 mm in diameter) subcortical infarcts resulting from occlusion of a single perforating artery,1 has been regarded as the least severe subtype of ischemic stroke for many years. Indeed, case-fatality rates are low, near 2.5% at 1 month, and, according to most studies, the risk of recurrence at 1 year is also low.2–4 Nevertheless, lacunar infarcts are still a major cerebrovascular issue. On the one hand, from a pathophysiological point of view, small vessel disease has been attributed to lipohyalinosis secondary to high blood pressure, but also to diabetes and hypercholesterolemia.5,6 However, these data remain a matter of controversy because most of the studies are hospital-based, which makes comparison difficult because of differences between hospitalized and nonhospitalized patients in the prevalence of risk factors.7 With the rise in the prevalence of diabetes and hypercholesterolemia in Western countries, the incidence of lacunar infarcts is expected to increase over coming years. On the other hand, the functional outcome is not as good as previously thought, with 42% of dependent patients at 3 years,8 an average annual death rate of 2.8%,2 and an increased risk of dementia.8 Consequently, lacunar infarcts should be considered as true markers of cerebral small vessel disease with implications on patient outcome.
Population-based studies are needed to evaluate trends in the incidence of cerebral lacunar infarcts and associated risk factors to monitor the effects of preventive strategies. We previously reported general data about epidemiological trends of strokes in the Dijon Stroke Project.9 Here, in this clinically pertinent complementary study, we aim to focus on specific data concerning the incidence, risk factors, and case fatality rates of cerebral lacunar infarcts from 1989 to 2006 using the same ongoing population-based stroke registry.
The incidence and prognosis of lacunar stroke were studied in patients included from 1989 to 2006 in the prospective population-based stroke registry of Dijon, which complies with epidemiological criteria for stroke incidence studies.10
The studied population comprised residents of Dijon, a town in France with a total population of 150 138 inhabitants (69 321 men and 80 817 women) in 1999. To be included, patients who had a first-ever stroke had to reside in the city of Dijon at the time of the stroke.
To ensure the completeness of case ascertainment, information was provided by 6 sources11: (1) from the emergency rooms, and all of the clinical and radiological departments of Dijon University Hospital, with a diagnosis of stroke made by one of the neurologists of the Department of Neurology, where the Stroke Registry is located; (2) from the emergency rooms and all of the clinical departments of the 3 private hospitals of the city and its suburbs with diagnosis made by private neurologists working in these establishments; (3) from the patient’s home or from the nursing homes of the city with diagnosis assessed by the 250 general practitioners with the help of an outpatient clinic with either a public or private neurologist who notified and registered the case; (4) from the 3 private radiological centers where the medical records were reviewed to identify missed cases that had not been transferred to the Registry by the general practitioners; (5) from the ultrasound Doppler centers of the University Hospital and private centers where medical records were reviewed; and (6) from the death certificates obtained from the local Social Security Bureau that is responsible for registering all deaths in the community to identify fatal strokes occurring in nonhospitalized patients. Hence, all of the information collected by the various correspondents was continuously centralized in the Stroke Registry.
Stroke was defined according to World Health Organization recommendations12 and according to the International Classification of Disease.13 Clinical diagnoses of stroke were validated by a CT or, since 1997, by MRI. All subsequent strokes occurring 28 days or more after first-stroke onset were recorded as recurrent stroke and were therefore not considered in this study. The diagnosis of ischemic stroke subtype was always performed on clinical and cerebral imaging. Symptomatic lacunar infarct was defined as a stroke presenting one of the 5 classic lacunar syndromes (pure motor stroke, pure sensory stroke, sensorimotor stroke, ataxic hemiparesis, and dysarthria–clumsy hand syndrome) and confirmed by small (<15 mm in diameter) subcortical infarct on brain CT scan or MRI in the absence of any other morphological cause of ischemic stroke found on the neuroimaging examination.
We collected classical cerebrovascular risk factors with the same methodology previously described.9 Hypertension was listed if there was a history of known hypertension with or without antihypertensive treatment with a systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥95 mm Hg. Diabetes mellitus was recorded if a glucose level of ≥7.8 mmol/L had been reported in the patient’s medical history or was found in the blood sample taken at the time of the stroke (patients who had been treated with insulin or oral hypoglycemic agents were also considered diabetics). Similarly, hypercholesterolemia was recorded for total cholesterol level ≥5.7 mmol/L or triglyceride level ≥1.6 mmol/L. To ensure the comparability of our results, we kept these cutoff values throughout the study period although the definitions of both hypertension and hypercholesterolemia changed with time. We also recorded smoking (more than one cigarette per day, current or former habit), previous myocardial infarction, angina, peripheral vascular disease, and atheroma of cervical arteries diagnosed by ultrasound scan. Atrial fibrillation was diagnosed on electrocardiogram or Holter recordings. Two-dimensional echocardiography (transthoracic or transesophageal cardiography) was performed to detect other cardioembolic sources. Carotid and vertebral ultrasonography as well as standard blood and urine tests were performed. A history of transient ischemic attack, defined as sudden development of signs and symptoms affecting motor, sensory, sensorial and speech, brainstem, and cerebellum functions lasting less than 24 hours, was considered a cerebrovascular risk factor.
Our registry was approved by the National Ethics Committee (CNIL) and complies with national rules on informed consent of patients.
To measure the incidence rates, the National Institute of Statistics provided census data for 1982, 1990, and 1999 concerning the population in Dijon in l-year age groups and by sex. The population was estimated from these censuses by linear interpolation from 1989 to 1999 and then by extrapolation after 1999. The crude incidence rate per age group and the standardized rate in terms of world populations were calculated for every year and according to sex by the use of the direct method with the SEGI 1996 world population.14 We assumed POISSON distribution for the annual number of events to calculate 95% CIs for the rates.
The Pearson χ2 test was used to compare the proportion of cerebrovascular risk factors in lacunar and nonlacunar strokes.
For the period 1989 to 2004, vital status at 2 years was found in 96% of patients. Survival rates after stroke were estimated by the Kaplan–Meier method. Comparison between groups was performed by the log rank test. A Cox regression model, adjusted for age and sex, was used to determine the effect of lacunar stroke versus nonlacunar strokes on death at 2 years. CIs were calculated using the Greenwood method.
Statistical analysis was performed with STATA 9.0 software.
From 1989 to 2006, a total of 2536 incident ischemic strokes were recorded. Of these, using clinical and brain neuroimaging data, 715 (28%) were classified as lacunar stroke (354 men and 361 women) and 1821 were identified as nonlacunar stroke (831 men and 990 women; Table 1). Over the 17-year period, there was no significant change in the proportion of lacunar infarcts among ischemic strokes. The proportion of patients with lacunar stroke who underwent CT or MRI examination is presented in Table 2. A significant increase in the use of MRI examination was observed since 1997, whereas the proportion of lacunar patients with a CT scan still remained stable with time.
Figure 1 shows age-specific incidence of lacunar infarcts by sex. We observed a progressive increase in the incidence with each decade of life. The rise was particularly pronounced from the age of 70 years in both men and women. Mean age at lacunar infarct onset was 71.7 (95% CI, 68.7 to 74.6) years in the first study period and 72.8 (95% CI, 69.9 to 75.7) years in the last one in men and, respectively, 75.1 (95% CI, 71.3 to 78.9) and 74.8 (95% CI, 72.6 to 77.3) years in women. The change in mean age at onset was not significant in either men (P=0.58) or women (P=0.91).
In the whole study period, standardized incidence rates according to world populations were 18.3 per 100 000 per year in men and 10.3 per 100 000 per year in women. The incidence of lacunar infarcts was significantly lower in women than in men (rate ratio, 0.69; 95% CI, 0.525 to 0.706; P<0.001). Table 3 shows trends in incidence rates by study periods in men and women and in young (younger than 65 years old) and old (older than 65 years) patients. Over the 17 years, there was a trend toward an increase in the incidence rates of lacunar infarcts, but the variation was not significant in either men or women. When both sexes were considered together, the rate ratio for overall incidence of lacunar infarcts was significantly suggestive of an increase in incidence (rate ratio, 1.02; 95% CI, 1.0055 to 1.0346; P=0.007). According to the age, a significant increase in the incidence was observed in young patients (rate ratio, 1.049; 95% CI, 1.0175 to 1.0817; P=0.002), whereas the incidence was stable in old patients.
Table 4 shows the distribution of cerebrovascular risk factors by study periods and in the whole study period in patients with lacunar and nonlacunar ischemic stroke. A history of atrial fibrillation was significantly more frequent in patients with nonlacunar ischemic stroke (31%; 95% CI, 0.29 to 0.33) than in lacunar infarcts (15%; 95% CI, 0.13 to 0.18; P<0.001). We did not find any significant difference in the distribution of the other cerebrovascular risk factors.
Figure 2 presents Kaplan–Meier estimates of survival rates among patients with lacunar and nonlacunar ischemic stroke diagnosed from 1989 to 2004. In lacunar infarcts, survival rates were evaluated at 96% at 1 month (95% CI, 0.94 to 0.97), 86% at 1 year (95% CI, 0.83 to 0.89), and 78% (95% CI, 0.75 to 0.81) after 2 years of follow-up. Concerning nonlacunar ischemic strokes, these were, respectively, 82% (95% CI, 0.80 to 0.84), 68% (95% CI, 0.66 to 0.71), and 62% (95% CI, 0.59 to 0.64). The survival rate after lacunar infarcts was significantly higher than that after nonlacunar ischemic strokes (hazard ratio, 2.05; 95% CI, 1.70 to 2.47; P<0.001).
Our standardized incidence rates of lacunar stroke were similar to those observed in other Western countries.3,15–17 Nevertheless, comparisons are not always easy. Actually, on the one hand, classifications used to define lacunar infarct vary from one study to another depending on whether a clinical, radiological, or pathological point of view is taken. On the other hand, the denominators used to calculate standardized rates are different.
Over the 17 years, we observed a significant increase in the incidence of lacunar stroke in both sexes considered together, whereas the rise was not significant when men and women were considered separately. This discrepancy could be explained by the small number of recorded cases of lacunar stroke, which made it difficult to obtain significant trends from a statistical point of view. One remarkable finding of our study is the increase in the incidence of lacunar stroke only in patients younger than 65 years of age. This result probably points to a lack of efficacy in the primary prevention of cerebrovascular disease. It is also an argument that demonstrates the need to develop stroke care units to improve the management of these young patients in the acute phase of stroke in the future.
Our results contrast with the decrease in lacunar stroke observed in the Hisayama study, Japan, between 1961 and 1988.18 It is well established that small artery lesions are more common in Asian countries, probably due to the higher prevalence of high blood pressure and a typical Asian diet, and the improvement in hypertension control could have led to the decline in lacunar stroke in these countries. In our population, we previously hypothesized that a lack of control of high blood pressure associated with a rise in the prevalence of diabetes and hypercholesterolemia could explain the increase in lacunar strokes.9 The pathophysiology of lacunar infarcts is classically characterized by segmental arterial disorganization or lipohyalinosis secondary to the effects of hypertension. This hypothesis suggests that lacunar stroke is correlated with hypertension as first recognized by Fischer.19 However, some studies have shown that the profile of risk factors is not specific to lacunar infarction but is largely similar to other stroke subtypes.7,16,20 Like previous studies,7,16,20 we did not find a significantly higher proportion of arterial hypertension in patients with lacunar infarcts than in those with nonlacunar stroke (69% versus 65.9%, P=0.14). In contrast, a significantly higher prevalence of arterial hypertension and diabetes has been reported in lacunar than in nonlacunar stroke according to a recent review of studies assessing risk factor profiles in various ischemic stroke subtypes.21 Nevertheless, there were statistical discrepancies between the results of the individual studies, and classification bias was of particular importance. When only studies using risk factor-free classification were considered, ie, classification in which risk factors are not used to classify ischemic stroke into one of the different etiological subtypes, the apparent excess of hypertension and diabetes in lacunar versus nonlacunar strokes disappeared, which is in accordance with our results. Hence, to avoid classification bias, the diagnosis of ischemic stroke subtypes should be based solely on clinical and radiological features and not include etiological assumptions about risk factors. Moreover, most of the studies were hospital-based, which could have led to another bias because of differences in the prevalence of risk factors between hospitalized and nonhospitalized patients.7
We also observed a significantly greater prevalence of chronic atrial fibrillation in nonlacunar stroke than in lacunar infarcts (31% versus 15.5%, P<0.001). This is probably due to the high prevalence of atrial fibrillation in cardioembolic infarcts (78.5%) included in nonlacunar strokes. This result is similar to the 10% to 15% of patients found to have a major cardioembolic source who present with a lacunar stroke,15,17,20 and the implication of cardiogenic emboli in lacunar infarcts is a subject of controversy.20 Nevertheless, our results support the view that cardiogenic embolism is not a common cause of lacunar infarcts.
Compared with nonlacunar stroke, lacunar stroke was associated with a more favorable prognosis of survival. Patients with lacunar infarct were twice as likely to be alive at 2 years compared with patients with other ischemic stroke subtypes. In a recent review2 based on 6 population-based studies evaluating prognosis after lacunar infarction and referring to a total of 462 patients, the mean case fatality was 2.5% (range, 0% to 10%) at 30 days and 2.8% (range, 2% to 15%) at 1 year. It was, respectively, 3.8% and 13.6% in our study, which is very similar to the results of the L’Aquila registry.16 The difference between survival in lacunar versus nonlacunar strokes was observed in the first 90 days (Figure 2). After this delay, trends in survival rates appeared to be very similar suggesting that better survival in patients with lacunar stroke mostly depended on low early mortality. This finding is probably related to the small volume of the infarct. However, despite this relatively good prognosis in terms of survival, lacunar stroke is not as favorable in terms of sequelae. Indeed, in the long term, there is a higher risk of developing cognitive dysfunction. This has been evaluated in a number of studies in which dementia was reported in 11% of patients 2 to 3 years after lacunar infarct8,15 and in 15% after 9 years.22 Consequently, with the rise in the incidence of lacunar stroke reported here, we may assume that the incidence of vascular dementia increased over the study period. Our data did not allow us to verify this hypothesis and it will be interesting to focus on this major point in a further study.
The major advantage of our study is the continuous and well-defined ascertainment from 1989 to 2006 in a small population and the collaboration of numerous investigators from all fields of patient management, which ensured the exhaustiveness of case ascertainment. In addition, the population of the city was very stable, with less than 5% of migration, which avoids bias due to changes in ethnic mix, and there was no change in the economic status of local residents. Diagnosis of the stroke subtype was precise thanks to neuroimaging because CT was performed in more than 98% of cases.
However, our study has several possible limitations. Although methods for case ascertainment and criteria for lacunar stroke were consistent throughout the study period, the incidence could have been overestimated in the last study periods because of the improvement in diagnostic techniques with the use of MRI. In our study, overall cases were ascertained prospectively, and there was probably no bias in the diagnosis of lacunar strokes, because the definition of cases did not change over time, contrary to other ischemic subtypes in which TOAST classification23 was retrospectively applied to improve the quality and reliability of our registry. However, MRI examination was introduced for the diagnosis of stroke in 1997, and it has been demonstrated that diffusion-weighted MRI is clearly superior to CT in the detection of lacunar infarct with a sensitivity of nearly 95%.24 Nevertheless, access to this technique remains limited. From 1997 to 2006, only 26% of patients with lacunar stroke had MRI examination (Table 2). In addition, a significant rise in the incidence of lacunar infarcts was observed in the previous period, from 1989 to 2000, in women (P=0.013) and both sexes together (P=0.011), suggesting that we cannot restrict this trend to a diagnostic bias all the more so because the proportion of patients with lacunar stroke who underwent CT was stable throughout the study period. The second limitation is that >5% data for smoking were missing and consequently not evaluated in the comparison of risk factors between lacunar and nonlacunar strokes. In addition, vital status at 2 years was obtained in 96% of cases, whereas at 5 years, it was only present in our files in 92% of cases. As a consequence, there could be a bias in evaluating survival at 5 years because of missing data. However, despite this shortcoming, trends in survival rates in patients with lacunar and nonlacunar stroke at 5 years and at 2 years were parallel, which strengthens the hypothesis that it is the first 90 days that make the difference.
In conclusion, in our continuous population-based study, we observed a significant rise in the incidence rates of lacunar infarcts even when any classification biases are taken into account. This underlines the need to develop effective preventive strategies, although we have confirmed the results of previous population-based studies, which also found that the association among hypertension, diabetes mellitus, and lacunar stroke was no stronger than the association between these 2 risk factors and nonlacunar stroke. As previously reported, because of lower early mortality, the prognosis for lacunar stroke in terms of survival is better than that for other subtypes. However, because of risk of recurrence and cognitive dysfunction, lacunar stroke is not benign.
We thank the University Hospital and the Faculty of Medicine of Dijon, the Community Association Grand-Dijon, the General Council of Côte d'Or, the Burgundy Health Agency, Regional Council and University, Inserm, and Institut de Veille Sanitaire for their help. We also thank Mr Philip Bastable for reviewing the English.
- Received November 24, 2007.
- Accepted December 5, 2007.
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