Correlation of intracranial atherosclerosis with carotid stenosis in ischemic stroke patients.

INTRODUCTION: Carotid stenosis is a major risk factor for ischemic stroke. However, the effect of carotid stenosis on the site of stroke is still under investigation. AIMS: This study aimed to elucidate how the presence of carotid stenosis influenced the pattern of stroke and also how it interacted with other risk factors for stroke.
MATERIALS AND METHODS: Thirty-eight patients with ischemic stroke were included in this study and were investigated with carotid artery Doppler and magnetic resonance angiography for carotid stenosis and intracranial stenosis in the circle of Willis, respectively. Other known risk factors of stroke were also studied in and compared between the subgroups with and without carotid stenosis.
RESULTS: In patients without carotid stenosis, anterior cerebral artery was the commonest site of stenosis. In patients with carotid stenosis, middle cerebral artery was the commonest site of stenosis. Overall, middle cerebral artery was the commonest territory of stroke. Patients with hypertension, diabetes and history of smoking had preferential stenosis of the anterior cerebral artery.

Introduction

Stroke is the foremost cause of disability across the world. In United States, 800,000 patients have stroke every year; 87% of them have ischemic stroke.[1] Again, 87% of all stroke-related deaths occur in low-to middle-income nations.[2] In India, age-standardized prevalence rate of stroke is 545 per 100,000 and mortality rate in stroke is 7.5 per 1000.[3]

Carotid stenosis is an established risk factor of ischemic stroke. In patients with carotid stenosis < 75%, annual incidence of stroke is 1.3%.[4] Intensive medical management of carotid stenosis can reduce the risk of stroke to 0.34%.[5] On the other hand, ischemic stroke patients have a higher likelihood of having carotid stenosis. However, the site of stroke is not clearly related to the degree and site of the carotid stenosis.

The incidence of intracranial atherosclerosis is high in Asians. Outcome of stroke is poor in this group, with a mortality of 101-125 per 100,000 patients.[1] Recent studies have shown that the outcome of stroke deteriorates and risk of recurrent stroke increases with intracranial atherosclerosis.[6] Stenosis of the major intracranial vessels progresses at the rate of 9-12% over six months and a patient with more than 50% stenosis has approximately 40% risk of suffering a vascular event over the next two years.[7] Intracranial atherosclerosis has been shown to correlate well with atherosclerosis at other sites like carotid arteries and the aorta.[8]

Materials and Methods

A cross-sectional descriptive study was conducted at multiple tertiary care centers during a period of two years between 2009 and 2011. The institutional ethics committee approved the study protocol prior to the commencement of the study. Patients admitted with first occurrence of ischemic stroke were included in the study. All participants provided an informed consent for inclusion as study subjects. Critically ill patients and those who were unwilling to participate in study were excluded.

The participants underwent clinical examination at the time of admission. Information regarding demographic background and risk factors were collected. Initial blood investigations included complete blood count, blood glucose, renal and liver function tests, lipid profile and electrolytes. Dyslipidemia was defined as the presence of any one of the following — high-density lipoprotein < 40 mg/dl, low-density lipoprotein > 130 mg/dl. Atrial fibrillation was defined as documentation of the same in at least one electrocardiograph recording at any point of time.

Each patient underwent magnetic resonance imaging (MRI) of brain in a 1.5 Tesla Toshiba scanner with 8-channel head coil. The MRI protocol included T1, T2, T2-FLAIR and DWI sequences. At the same time, time-of-flight magnetic resonance angiogram (TOF MRA) was obtained. The sites of stenosis in the intracerebral circulation were compared in subgroups based on age, risk factors and extent of carotid artery stenosis. All statistical computations were performed with R programming language.

Results

The summary of the demographic variables of the patients and prevalence of the risk factors are shown in Table 1. The study population was predominantly male and hypertension was identified as the commonest risk factor among the patients. Total 11.11% patients had anterior cerebral artery (ACA) territory stroke, 55.56% had middle cerebral artery (MCA) territory stroke and 36.11% had posterior cerebral artery (PCA) territory stroke.

Table 1

Demographic and risk factors in the study population

Intracranial stenosis was found in 52.78% patients and extracranial stenosis was found in 13.89% patients. Among the patients who had extracranial stenosis, 80% patients had concurrent intracranial stenosis. The relationship between the site of stroke and the sites of arterial stenosis is shown in Table 2. In patients with internal carotid artery (ICA) stenosis greater than or equal to 70%, stem of the MCA was the most prevalent site of stenosis, followed by ACA. In those who had ICA stenosis less than 70%, A1 segment of the ACA was the commonest site of stenosis. Overall, ACA was the commonest site of stenosis, even though MCA was the commonest territory of stroke.

Table 2

Relationship between site of stroke and site of arterial stenosis. All the figures are in percentage points

Table 3 shows the relationship of the risk factors to the site of stenosis. Notably, hypertension, diabetes and smoking had stronger association with ACA stenosis. On the other hand, all patients with atrial fibrillation had MCA stenosis.

Table 3

Relationship of risk factors and site of intracranial stenosis

Discussion

The burden of intracranial atherosclerosis has been reported in different populations worldwide. The incidence of intracranial atherosclerosis is very high in northern India and it is responsible for 30-50% of ischemic strokes in Asian population.[9] Major risk factors for intracranial atherosclerosis are hypertension, diabetes, smoking and dyslipidemia.[10] Stenosis of the large branches of the Circle of Willis can lead to stroke by hypoperfusion or by artery-to-artery embolism.[11] Our study shows three aspects of intracranial atherosclerosis. First, it shows the spatial pattern of stenosis. Second, it correlates the pattern with the presence of carotid artery stenosis. Third, it re-evaluates the relationship of intracranial pathology with the risk factors.

Carotid artery stenosis contributes significantly to the total burden. Patients with more than 70% stenosis of carotid artery had a stroke rate of 28% at 18 months.[12] Carotid artery stenosis can lead to stroke by multiple mechanisms - embolism, thrombotic occlusion, dissection or hypoperfusion. On the other hand, carotid stenosis is considered as a marker of systemic atherosclerosis and has a significant correlation with myocardial infarction.[13] Therefore, the correlation of carotid stenosis with intracranial atherosclerosis becomes a pertinent topic of investigation. Also, in patients with coexistent stenosis of intracranial and extracranial vessels is expected to alter the pathophysiology of stroke. We have investigated the spatial aspect of this process. Our results show that patients with extracranial stenosis almost always have associated intracranial stenosis but the reverse is not true in the majority. Another important aspect of our results is that ACA stenosis, rather than MCA stenosis, was present in greater proportion of patients. The reason why ACA stenosis is less likely to manifest as stroke is not clear and requires further evaluation.

Risk factors for carotid artery stenosis and intracranial stenosis are largely similar, and include age, hypertension, diabetes mellitus, smoking and dyslipidemia. We have included ischemic heart disease as well as a marker of systemic atherosclerosis. In our study, all the risk factors except ischemic heart disease and atrial fibrillation were associated with ACA stenosis. No risk factor preferentially caused atherosclerosis in multiple territories. Concurrent atherosclerosis in extracranial and intracranial arteries was also studied. Hypertension emerged as the strongest risk factor for concurrent stenosis, followed by diabetes and dyslipidemia. Hypertension was similarly indicted in literature as well.[14]

Main limitations of our study are the small number of patients and lack of invasive studies. According to the Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial, cerebral catheter angiography (CTA) is the gold standard for the diagnosis of intracranial atherosclerosis and not MRA, though both methods fail to accurately detail the degree of intracranial stenosis.[15] Fractional flow reserve identifies hemodynamically significant pressure gradient across stenotic lesions. TOF circle of Willis images often overestimate the degree of stenosis in the presence of significant neck vessel stenosis. However as non-invasive methods, TOF MRA and high resolution MRI are getting wide recognition.

In conclusion, we would like to state that ACA was the most prevalent site of stenosis in patients without ICA stenosis and had the strongest association with risk factors like hypertension, diabetes and smoking, even though MCA territory is the commonest affected by stroke. Additionally, presence of ICA stenosis was associated with MCA stenosis in preference to other sites. The biological reason for this pattern needs to be studied in larger populations.