Prevalence of middle cerebral artery stenosis in asymptomatic subjects of more than 40 years age group: A transcranial Doppler study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.144443
Source of Support: None, Conflict of Interest: None
Introduction: Middle cerebral artery (MCA) disease is the most common vascular lesion in stroke. Transcranial Doppler (TCD) is a non-invasive bedside screening method for assessing cerebral blood flow. Aim: To investigate the prevalence of MCA stenosis in asymptomatic but high-risk individuals for stroke. Materials and Methods: Prospective study between December 2011 and December 2013. Vascular risk factors considered included: hypertension (HTN), diabetes mellitus, smoking, alcohol consumption, coronary artery disease (CAD), peripheral vascular disease (PVD), hypercholesterolemia and obesity. TCD was performed with portable machine through the temporal windows by use of a standardized protocol. Results: Of the 427 subjects, 374 were analyzed; males 264 (70.6%) and females 110 (29.4%). Mean age was 54.2 ± 7.6 years. The frequency of the risk factors was: HTN 287 (76.7%), diabetes 220 (58.8%), CAD 120 (32.1%), hypercholesterolemia 181 (48.4%), smoking 147 (39.3%), alcohol 99 (26.5%), obesity 198 (52.9%) and PVD 8 (2.1%). Of the 374 subjects, 27 (7.2%) had intracranial arterial stenosis and the rest had normal intracranial arteries. On univariate analysis, subjects with higher age, HTN, CAD, smoking and hypercholesterolemia had higher risk of having intracranial arterial stenosis (P < 0.05). Multivariate analysis showed HTN and CAD are independent risk factors for intracranial arterial stenosis. Conclusions: Overall prevalence of intracranial arterial stenosis is 7.2% in high-risk population sample from Hyderabad in South India. HTN and CAD are independent risk factors for the development of intracranial arterial stenosis.
Keywords: Asymptomatic, middle cerebral artery, stenosis, stroke, transcranial doppler
The prevalence of vascular risk factors and cerebrovascular subtypes differ among various populations. Intracranial large artery disease is the most common vascular lesion in stroke of South Asians, including Indians compared to European American. ,,,, Most studies have focused on the frequency and the risk factors of patients after stroke or transient ischemic attack (TIA) but studies among asymptomatic subjects are rare. The presence of intracranial atherosclerosis carries a high risk of further vascular event and death. , There is emerging evidence for dual antiplatelet therapy and revascularization in intracranial large artery diseases.  Previous studies found that intracranial large artery disease was prevalent among 69% to 84% of ethnic South Asians with large artery stroke. , Population-based screening is the best scientific approach but the yield among patients without vascular risk factors is low. Targeting high-risk individuals gives higher yield. Many studies of intracranial circulation in symptomatic patients are on record. , A few studies on abnormalities of intracranial circulation in high risk asymptomatic patients have been recently reported. ,,
The diagnosis of intracranial arterial stenosis or occlusion requires vascular imaging of the cranial circulation. For decades, conventional contrast angiography has been the only method to visualize the intracranial circulation in clinical practice. The invasive nature of conventional angiography and the risk of perioperative complications hinder its widespread use in the study of intracranial vascular lesions in stroke patients.  Given the disadvantages of Digital Subtraction Angiography (DSA), Magnetic resonance angiography (MRA) and computerized tomography (CT) angiography have emerged as feasible noninvasive techniques to evaluate the intracranial vasculature.  Even though MRA and CT angiography has good correlation compared to DSA, the former cannot be used for routine screening purpose in non stroke patients because of cost factor and limited availability.
Transcranial Doppler (TCD) study is a convenient, non-invasive, non-ionizing, inexpensive bedside screening method for assessing cerebral blood flow velocities. Aaslid introduced the term "Transcranial Doppler" in 1982. He also reported the first results of TCD examination of basal cerebral arteries.  TCD ultrasonography is a noninvasive ultrasonic technique that uses a hand-held low frequency [i.e. 2-2.5 megahertz (MHz)] sector transducer that sends fixed or pulsed sound waves to measure the velocity of blood flowing in the basal arteries of the brain. Sound waves are transmitted through temporal, orbital and suboccipital acoustic windows of the skull. When the sound waves come in contact with blood, they are reflected off the red blood cells through the brain and skull to a detector. The velocity of the sound waves reflected to the surface changes because the blood cells themselves are in motion toward, or away from the sound wave detector. This is called Doppler shift and is directly related to the velocity and flow of the blood cells. The velocity of the blood cells is faster during systole and slower during diastole. TCD measures flow velocity of the middle cerebral, anterior cerebral, posterior cerebral, vertebral, basilar, internal carotid and ophthalmic arteries.
For diagnosis of intracranial large artery occlusive disease, TCD comparison with DSA, MRA, CT angiography has been reported. ,,,,,,, For all vessels, TCD had a sensitivity of 93.8% and specificity of 92.1% but for MCA, TCD had a sensitivity of 100% and a specificity of 96.9% compared to MRA.  In countries like India (Asian countries), routine screening with TCD for intracranial steno-occlusive disease in high-risk asymptomatic population may be useful. Recently similar studies were done in Chinese population with TCD, , which showed significant correlation for intracranial stenosis in high risk asymptomatic non stroke population. Does Indian high-risk population for stroke have significant intracranial stenosis or not? Similar data is not available. To answer at least some extent of above question, this study was undertaken.
Aims of the study
To assess the prevalence of intracranial arterial stenosis in asymptomatic individuals for stroke with various vascular risk factors by means of screening with TCD ultrasonography and also to assess if there is any difference among the various vascular risk factors for causing intracranial arterial stenosis in asymptomatic individuals for stroke; and to investigate the independent association of risk factors for intracranial arterial stenosis.
The present study was a prospective study and conducted between December 2011 and December 2013. The design of the study was approved by the University Ethics Committee, Nizam's Institute of Medical Sciences. Five patients per week, on a first come first served basis were enrolled consecutively from the outpatient department. All subjects gave their written informed consent to take part in the study. Inclusion criteria were: Subjects more than 40 years and both genders and high risk but asymptomatic for stroke (at least one vascular risk factor). Exclusion criteria were: History of stroke/TIA; unable to give consent; uncooperative patients; and poor/incomplete echo window for TCD.
Demographic and past medical history including age, gender, hypertension (HTN), diabetes mellitus (DM), hypercholesterolemia, coronary artery disease (CAD), smoking and body mass index (BMI) were recorded. We measured height, body weight, blood pressure, fasting serum lipids and fasting blood glucose. High risk but asymptomatic for stroke population was defined as per the modified Framingham clinical assessment criteria.  According to this HTN, DM, history of smoking, excessive alcohol, CAD, peripheral vascular disease (PVD), high cholesterol and obesity were taken as vascular risk factors. We defined HTN as persistent systolic blood pressure >140 mm of Hg or diastolic blood pressure >90 mm of Hg, a clear history of HTN or on medication, or both. Subjects with DM were those with documented diabetes in their medical record, or fasting plasma glucose above 126 mg/dL or those who have taken drugs used for diabetes treatment. History of smoking included self-reported habit of past or current smoking. We defined habitual alcohol drinking when subjects self-reported habitual alcohol drinking in the past or present.  Cardiovascular disease included history of Myocardial infarction or angina. PVD meant past history of PVD or present active PVD. Fasting cholesterol >200 mg/dl was taken as hypercholesterolemia.  Obesity was defined as BMI of >30 kg/m 2 . 
TCD was performed with portable machine (Multi-dop® B + DWL), which is a 2 MHz, power motion single-channel TCD. We studied the bilateral middle cerebral arteries through the temporal windows by use of a standardized protocol.  The locations of the arterial segment under study are illustrated in [Figure 1]. We recorded insonation depth, peak systolic velocity, end diastolic velocity, mean flow velocity for all vessels. Cerebral arteries that could not be insonated because of poor acoustic windows were excluded from the study. We diagnosed the presence of intracranial arterial stenosis according to the peak flow velocity based on published criteria which was validated against MR angiography and clinical outcomes.  Briefly, the criteria for stenosis of arteries were defined by the peak systolic flow velocity more than 140 cm/sec for the middle cerebral artery (MCA). 
Data was entered in a spreadsheet and statistical evaluation was done using the IBM SPSS Statistics 20. Descriptive statistical values like mean and standard deviation (SD) were calculated for parameters required. Chi square test was used for various risk factors comparing between normal intracranial arterial group and stenotic intracranial arterial group. Mean age between stenotic and non stenotic group was compared using Independent sample T test. Chi square test was also used for comparing sex in the intracranial stenotic arterial group. Univariate and multivariate analyses were also done to know the predictors of intracranial arterial stenosis.
We examined a total of 427 subjects, of which 53 (12.4%) were excluded from the study because of poor/incomplete echo window for TCD and remaining 374 subjects were analyzed. Males were 264 (70.6%) and females were 110 (29.4%). Mean age was 54.2 ± 7.6 (Range 41-85 yrs).
The overall risk factors were HTN in 287 (76.7%), DM in 220 (58.8%), CAD in 120 (32.1%), hypercholesterolemia in 181 (48.4%), smoking in 147 (39.3%), alcohol in 99 (26.5%), obesity in 198 (52.9%) and peripheral arterial disease in 7 (1.9%) as shown in [Table 1].
Twenty-seven (7.2%) of 374 patients had intracranial arterial stenosis and 347 (92.8%) had normal intracranial arteries. TCD on a patient with peak systolic flow velocity >140 cm/sec is shown in [Figure 2].
Mean age was 58.3 ± 4.3 years. The overall risk factors in stenotic group were HTN 26 (96.3%), DM 20 (74.1%), CAD 20 (74.1%), hypercholesterolemia 18 (66.6%), smoking 16 (59.3%), alcohol 10 (37%), obesity 19 (70.4%) and peripheral arterial disease 1 (3.7%) as shown in [Table 2]. The differences in patient characteristics between those with and without intracranial arterial stenosis are shown in [Table 2]. Stenotic group had higher mean age and higher number of HTN, DM, CAD, smokers, alcoholics, hypercholesterolemia, PVD and obese subjects compared to non-stenotic group. The P value with Chi square test was calculated for various factors between non-stenotic versus stenotic group, which showed statistical significance (P < 0.05) for higher mean age, HTN, CAD, smoking and hypercholesterolemia. Even though DM, alcoholics, obesity and PVD was found in higher number in stenotic group, it did not reach statistical significance (P > 0.05).
In univariate analysis, associated indicators for stenosis include HTN (OR 8.6, P < 0.05), CAD (OR 7, P < 0.05), hypercholesterolemia (OR 2.3, P < 0.05), smoking (OR 2.4, P < 0.05), DM (OR 2.1, P > 0.05), alcohol (OR1.7, P > 0.05), PVD (OR 2.8, P > 0.05) and obesity (OR 2.2, P > 0.05) as shown in [Table 3]. Multivariate analysis, HTN and CAD are independent risk factors for intracranial arterial stenosis. Overall prevalence of intracranial arterial stenosis was 7.2% (27 of 374) in this study.
Ischemic stroke is a heterogeneous disease with a variety of pathophysiological mechanisms. Stroke prevention is of paramount importance. Recent successes in stroke prevention underscore the importance of targeting therapy specifically to remedy the underlying mechanisms, such as carotid stenosis and atrial fibrillation. Presence of intracranial stenosis is of clinical significance because it is an additional independent predictor for survival and recurrent events. Knowledge of intracranial disease in the symptomatic and especially the asymptomatic high risk population may be useful for evaluating future treatment modalities. There are marked differences in the distribution of arterial lesions among different populations. In white individuals, carotid stenosis is a common cause of cerebral ischemia. In contrast, intracranial large artery stenosis is the predominant vascular lesion found in patients of Asian, African, or Hispanic ancestry. ,,,, Previous studies found that intracranial large artery disease was prevalent among 69% to 84% of ethnic South Asians with large artery stroke. ,, Because of the large populations in Asia and Africa, intracranial large artery occlusive disease may be regarded perhaps numerically as the most common vascular cause of stroke in the world.
The present study is a prospective study to assess the prevalence of intracranial arterial stenosis in patients asymptomatic for stroke with various vascular risk factors. This is the first study from India about intracranial arterial stenosis in asymptomatic patients. The overall prevalence of intracranial arterial stenosis in this study was 7.2%. Previous studies have shown asymptomatic intracranial arterial steno-occlusion ranging from 6.9% to 16.4%. ,,,,
High prevalence in present study is probably because all studied patients had at least one vascular risk factor and majority of the patients have more than one vascular risk factor.
Intracranial stenosis is the most common stroke mechanism found in 26% of patients in our stroke registry and likely to be the common mechanism in other parts of India (personal communication). Detecting these patients at an asymptomatic stage will help to treat these patients aggressively to prevent the stroke. Association of intracranial stenosis with CAD in our patients emphasizes the need to screen for CAD in these patients. We have found that higher mean age, HTN, CAD, smoking and hypercholesterolemia were significant factors associated with intracranial arterial stenosis. These factors are well established factors for atherosclerosis. Our data is in agreement with previous community-based studies in China by Wong et al., ,,, non-community-based studies in Thailand by Suwanwela et al. and Japan by Uehara et al., , which reported that age, HTN, DM, CAD and hyperlipidemia were risk factors for intracranial stenosis. In this study, the frequency of DM was more in stenotic group compared to non-stenotic group but it was not of statistical significance. Probably this was due to the small sample size. In our study, DM, alcohol, PVD and obesity were not significant factors for intracranial arterial stenosis. This is also similar with most of the previous studies reported by Wong et al. ,
Univariate and multivariate analyses were also done in this study. Univariate analysis found HTN, hypercholesterolemia CAD and smoking as risk factors for the development of intracranial arterial stenosis. But multivariate analysis showed only HTN and CAD as independent risk factors for the development of intracranial arterial stenosis, which is almost similar to the previous published studies on this subject. ,
This study design is cross-sectional and only provides a snapshot of the health status as we did not know if the risk factors were present before or after the development of MCA stenosis. TCD is the only diagnostic tool used for this study without confirmation with angiography. We did not follow the stenosis group to assess rate of development of stroke over a period of time. In this study, the poor/incomplete window was found in 12.4%, which is similar to that reported previously. , This poor/incomplete window may over estimate or under estimate true prevalence of stenosis.
The risk factor assessment was based on self-reported response during the interview and minimal tests. Moreover, the study was conducted in a tertiary health care center. Further population-based studies are needed to confirm the prevalence of intracranial arterial stenosis. Nevertheless, this study provides an estimate of the burden of intra cranial atherosclerosis and allows clinical trials of various approaches to prevent stroke in this high-risk population.
The overall prevalence of intracranial arterial stenosis is 7.2% in high-risk non-stroke population in a sample from the South Indian city of Hyderabad. Higher mean age, HTN, CAD, smoking and hypercholesterolemia were significant risk factors for intracranial arterial stenosis. HTN and CAD are independent risk factors for the development of intracranial arterial stenosis.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]