Micro embolic signals in patients with cerebral ischaemic events.
The aim of this study was to evaluate the occurrence of micro embolic signals (MES) in patients with a cerebral ischaemia using transcranial doppler monitoring and to find out its diagnostic relevance. We prospectively performed bilateral multigated transcranial doppler monitoring from both middle cerebral arteries in 359 patients with an acute or recent (<4 weeks) cerebral ischaemic event, and in 182 control subjects without a cerebral ischaemic event. MES were analysed according to the standardised protocol. Patients with cerebral ischaemic events had a significantly higher (p<0.00001) rate of MES occurrence (31.8%) than control subjects (5.5%). MES were detected significantly higher in patients with partial or total anterior circulation infarcts (39.1%) than in those with lacunar infarcts (26.0%) or transient ischaemic attacks (27.3%). A correlation of MES and neuroimaging finding was also tried. TCD was found to have a predictive role in microemboli monitoring, predominantly in patients with large vessel territory infarction.
Stroke is one of the most common causes of motality and morbidity, especially for older population. Ischaemic strokes account for 80% of all strokes, and are most frequently caused by an embolic source., Transcranial doppler (TCD) sonography is a helful laboratory investigation for the diagnosis of cerebral embolism. These microemboli have been detected in various conditions including carotid arterial disease, prosthetic heart valves,, carotid endarterectomy, surgeries like cardiopulmonary by-pass, and in atrial fibrillation.
The aim of this study was to evaluate the occurrence of micro embolic signals (MES) in patients with a cerebral ischaemic event. Consequently, the data could help to define the reliability of MES detection by means and help of TCD.
In a period of 18 months, 400 consecutive patients with first cerebral ischemic event and 200 control subjects were investigated and studied. Control subjects were defined as patients without an ischaemic cerebrovascular disease. They suffered from idiopathic epilepsy (12 patients), multiple sclerosis (21 patients), possible Alzheimer's disease (13 patients), vertigo of peripheral origin (29 patients), peripheral nerve disease (46 patients), and Parkinson disease (61 patients). Forty-one patients and 18 control subjects were excluded from the study because of missing data (8 patients vs 2 controls), failed diagnostic procedures such as carotid doppler (9 patients vs 5 controls), and insufficient temporal bone window (24 patients vs 11 controls). The remaining 359 patients (219 males and 140 females; mean age 57.7±0.6 years) and 182 control subjects (97 males and 85 females; mean age 55.9±0.9 years) had undergone the routine clinical and diagnostic investigations including a general physical and neurological examination, a complete blood count, blood biochemistry, electrocardiogram, transthoracic echocardiography, carotid ultrasonography, a transcranial doppler sonography, and CT/MRI. None of the control subjects had any ischaemic lesions according to CT and/or MRI scan.
Clinical and neuroimaging classifications
Patients were allocated to one of the three groups according to presenting symptoms and signs: Transient ischaemic attacks (TIA); these patients presented with focal neurological symptoms, with abrupt onset and complete resolution within 24 hours.
Partial and total anterior circulation infarcts
(PACI/TACI); these patients presented with combination of higher cerebral dysfunction; homonymous visual field defect; and ipsilateral motor and/or sensory deficits of atleast two parts of the face, arm, or leg. Lacunar infarcts (LACI): these patients presented with a pure motor stroke, pure sensory stroke, sensory-motor stroke, or ataxic hemiparesis. Brain imaging patterns were categorised as acute territorial stroke patterns indicating large-vessel disease; lacunaes (<1.5 cm in diameter) and subcortical white matter lesions indicating smallvessel disease; and no ischaemic lesions.
Most of the TCD examinations were done within 7 days (73.8%) after the onset of the ischaemic event. According to our acute stroke management protocol, none of the ischaemic stroke patients were given any anti-thrombolytic therapy in the first week after the onset of stroke. TCD examinations were carried out and analysed by an experienced investigator who was unaware of the diagnosis of the patients or control subjects. TCD monitoring was performed with multigated transcranial doppler system (Multidop X4, DWL and TCD8 software). Long term monitoring was performed while the patients were at rest in the supine position. The first part of both MCAs were insonated simultaneously with a 2 MHz probe through the temporal bones at 50-60 mm depth. An intergate distance was settled at 5 mm. After stabilising the doppler signals, probes were fixed tightly with an elastic headband. Thirty minutes of computerised bilateral recording was carried out in every patient. All TCD examinations were carried out and analysed by the same observer (N.U.).
The established criteria for accepting the highintensity transient signals as MES were as follows:
< 100 ms, atleast 3 dB greater than the base-line activity, mostly undirectional, variable location in the TCD waveform, and having audible characteristic 'chirp' sound., Additionally, the proven MES was related to the time lag in occurrence of the two signals in the multigate technology [Figure. 1].,
Estimated risk factors
Patients and control subjects were considered to have hypertension if they had this diagnosis before the onset of stroke or admission, if they had sustained blood pressure of 160/95 mmHg or more on atleast two occasions during study evaluation or if patient received antihypertensive treatment throughout the entire study evaluation. Patients who had transient hypertension (Cushing's reflex) and had not received antihypertensive medication, were considered to be normotensive. Body mass index was calculated as weight in kilograms divided by height in meters squared. Obesity, was defined as 'body mass index of more than 25'. Diabetes mellitus was diagnosed if a subject had a previous diagnosis of diabetes mellitus or if the fasting blood glucose level was more than 120 mg/dl. The diagnosis of atrial fibrillation was based on ECG recordings. Coronary artery diseases consisted of angina pectoris (AP) and myocardial infarction (MI). These conditions were defined whether a patient or control subject had a previous medical record of AP or MI, or had a characteristic chest pain or discomfort (short duration, relieving by rest or nitroglycerin). Additionally, subjects with ECG changes indicative of myocardial damage or the diagnostic increases of serum enzyme levels were diagnosed as having coronary artery diseases. A current smoker was defined a one who smoked at least one cigarette a day within 6 months before the onset of stroke or admission. Alcohol abuse was determined, if the subject consumed more than 12gm pure alcohol per day within 6 months before the onset of stroke or admission. This is the limit for moderate drinking. High-grade carotid stenosis was diagnosed if a subject had a luminal narrowing of the internal carotid artery more than or equal to 70%.
MES were detected in 114 out of 359 patients and in 10 out of 182 control subjects (p<0.00001). Males had more MES than women, both in controls (7/3, male to female ratio; 2.3), and in patients (88/26, male to female ratio; 3.4). The rate of MES varied between 0 and 149 signals within 30 min (6.3±0.9 MES/30 min) in patients and between 0 and 44 within 30 min (1.1±0.3 MES/30 min) in control subjects. The highest number of MES were detected in both patients and controls, who had prosthetic heart valves. [Table I] summarises the clinical subgroups of patients. MES occurrences in the group of PACI/TACI were significantly higher than those groups of LACI and TIA.
The radiological findings showed significant differences between infarct types, considering MES occurrences. MES were found to be significantly higher in the territorial infarction than either in the lacunar infarctions or in the non-ischaemic lesion [Table II]. MES frequency was 87.2% (48/55) in symptomatic hemisphere in comparison to nonsymptomatic (7/55; 12.7%) in patients with territorial infarction. In patients with no ischaemic lesion, these frequencies were as follows; (20/24) 83.3% in symptomatic hemisphere, (3/24) 12.5% in non symptomatic hemisphere, and (1/24) 4.2% in both hemispheres. The distribution of risk factors for cerebral ischaemic events is summarised in the [Table III]. The most frequent risk factors among cases of cerebral ischaemic event were hypertension (58.8%), MES (31.8%), and current smoking (27.9%). In the univariate logistic regression analysis [Figure. 2], MES, hypertension, current smoking, coronary artery disease, obesity and high-grade carotid stenosis were significantly associated with the risk of cerebral ischaemic event. Although prosthetic heart valves had a higher rate of MES occurrence, it was not significantly associated with the cerebral ischaemic event. When multiple logistic regression analyses was performed [Figure. 3], the risk factors that remained independently significant were microembolic signals, hypertension and current smoking. We also did the univariate and multiple logistic regression analyses to find if there was any correlation between the occurrence of these risk factors and MES. Briefly, in multiple logistic regression analysis high grade carotid stenosis (OR: 7.98; 95% CI: 2.71-23.50; p=0.000), prosthetic heart valves (OR: 6.82; 95% CI: 2.25-20.65; p=0.001), coronary artery disease (OR: 2.47; 95% CI: 1.16-5.24), and atrial fibrillation (OR: 2.11; 95% CI: 1.04-4.26) were significantly and independently associated with MES in patients, whereas these risk factors were not present in control groups. However, in univariate analysis high grade carotid stenosis (Fisher exact Chi-square=166.4; p=0.000) and prosthetic heart valves (Fisher exact Chi-square=162.6; p=0.000) were significantly associated with MES in controls.
The diagnosis of embolic sources in cerebral ischaemic events has become interesting by recording MES by TCD. MES monitoring in acute cerebral ischaemia has been reported to be of help in determining the aetiology of stroke.,,,,,,,,, In addition, there are studies showing relation of MES with possible clinical processes. Presence of MES has been reported to be associated with the neurological deficits.,,,,
However, the relationship between neurological complications and MES as shown by TCD is not exactly known. In recent years, many studies have shown that MES may have importance in the pathogenesis of large vascular infarctions.,,,,,
The data presented here supports the potential clinical significance of MES in the pathogenesis of ischaemic cerebral events in patients with clinical symptoms and neuroimaging signs indicating large-vessel disease. The MES occurrence in patients (31.8%) was significantly higher than controls (5.5% p=0.00001).
Additionally, the highest rate of MES was found in patients with territorial infarction (39.9%) as compared to lacunar infarction (p=0.034). Though MES was detected in patients with lacunar infarct (26.7%) and no ischaemic lesion (26.7%), as well. The results were not statistically significant. The possible explanation of relatively higher MES occurrence in patients with lacunar infarct and non ischaemic lesions is the higher frequency of prosthetic heart valves in this study. In contrast, patients with territorial infarction had a relatively lower rate of prosthetic heart valves. Patients with prosthetic heart valves characteristically show a high frequency of MES., MES are more like gaseous particles generated by a cavitation mechanism, indicating a benign nature of microemboli, which arises from prosthetic heart valves.,, The single MES most likely reflect very small particle but rarely may represent emboli large enough to cause occlusion of the small vessels. Lacunar infarction has been noted in patients with potential sources of cerebral emboli in the heart or neck vessels. Patients with territorial infarction have a significantly higher rate of highgrade carotid stenosis (9.4%, p=0.015) than those with lacunar infarction (3.8%) or with non ischaemic lesion (1.1%). MES detected in patients with high-grade carotid stenosis are usually solid, and represent emboli with an increased risk of a stroke., Reduction of both the number of embolic signals and the risk of stroke after endarterectomy of high-grade carotid stenosis support this suggestion.,
The present study shows that MES were most frequent in symptomatic hemisphere in accordance with previous studies.,,,, MES were confined to the ipsilateral side in patients with high grade carotid stenosis, while patients with prosthetic heart valves, or with atrial fibrillation were found to have bilateral MES. This study also provides estimates of the relative risk of cerebral ischaemic event associated with various factors. The use of standardised criteria ensured the reliability of the comparison of risk factors. However, the selection of the patients with cerebral ischaemic event in MCA territory gave limitation to our study. Additionally, our study is a hospital-based study, and therefore it is not entirely representative of the general population. Nevertheless, our data indicates that hypertension, current cigarette smoking, and microembolic signals detected on TCD in multiple logistic regression analysis were significantly associated with cerebral ischaemic event in MCA territory. Similar to our findings, significant associations of hypertension and cigarette smoking have been reported in both hospital-based and Gucuyener et al population-based studies.,, Obesity, coronary artery disease and high-grade carotid stenosis were significant risk factors for cerebral ischaemic event in the univariate analysis, but were not significant in the multiple logistic analysis. Whereas, coronary artery disease and high grade carotid stenosis were found as the determinants of MES, the lack of an association between these factors and the risk of cerebral ischaemic event in our study could be related to the fact that patients with cerebral ischaemic events in the posterior circulation were excluded from this study. Secondly, there were less number of patients with high grade carotid stenosis in the present study.
In conclusion, our study supports that the TCD has a predictive role of microemboli monitoring, predominantly in patients with large-vessel territory stroke.