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Microembolic signals in subarachnoid hemorrhage
Journal of Clinical Neuroscience 16 (2009) 390–393
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Microembolic signals in subarachnoid hemorrhage q Mahmoud Reza Azarpazhooh a,*, Arash Velayati b, Brian R. Chambers c, Hossain Mashhadi Nejad d, Payam Sasan Nejad a a
Department of Neurology, Ghaem Medical Center, Mashhad University of Medical Science (MUMS), Taghi Abad Square, Mashhad 9196773117, Iran Division of Human Genetics, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran c Austin Health, National Stroke Research Institute, University of Melbourne, Heidelberg Repatriation Hospital, Heidelberg Heights, Victoria, Australia d Department of Neurosurgery, Ghaem Medical Center, Mashhad University of Medical Science, Mashhad, Iran b
a r t i c l e
i n f o
Article history: Received 16 February 2008 Accepted 19 May 2008
Keywords: Subarachnoid hemorrhage Microembolic signals Vasospasm
a b s t r a c t Microembolic signals (MES) detected by transcranial Doppler (TCD) have been reported in subarachnoid hemorrhage (SAH), although their origin and contribution to brain ischemia remain uncertain. We conducted a prospective study to evaluate the frequency of MES among patients with SAH and to determine their origin. Twenty-seven patients with SAH, comprising 15 aneurysmal and 12 non-aneurysmal patients, participated in the study. TCD evaluation was performed using a 2 MHz probe. Patients were studied three times per week during their in-patient stay to detect vasospasm, and then each middle cerebral artery (MCA) was monitored for 30 min using the Monolateral Multigate mode to detect MES. Using this method, MES were detected in 7 out of 15 patients (47%) with aneurysmal SAH and were not seen in non-aneurysmal patients (p = 0.007). Vasospasm occurred in 52% (14/27) of cases. However, clinical signs and symptoms of vasospasm were identified in only 18.5% (5/27). There was no significant relationship between MES and vasospasm (p = 0.224). Also, no relationship was found between MES and the location of the aneurysm (p = 0.685). Thus, in this study MES were only detected in aneurysmal SAH. However, we did not find a relationship between the location of the aneurysm and MES, or the presence of vasospasm and MES. Therefore, MES in patients with SAH may also originate from vascular pathology other than the aneurysm sac or vascular spasm. Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction Subarachnoid hemorrhage (SAH) is a serious form of stroke, with high morbidity and mortality largely attributable to the initial bleed, rebleeding, and vasospasm.1,2 The pathogenesis of cerebral vasospasm after SAH is not fully understood, but inflammatory responses and immunological reactions have been implicated.2 In a study of the brains of SAH patients who died shortly after the development of vasospasm, histological examination revealed white fibrin microthrombi associated with infarction in the territory of vasospastic arteries, corresponding to hypodensities on brain CT scans and neurological findings.3 The study proposed that damage to the endothelial wall from vasospasm might induce microthrombosis and embolism. Transcranial Doppler (TCD) is used routinely in some centres to monitor SAH patients for vasospasm. Microembolic signals (MES), which are brief, high-intensity transients that occur when particulate microemboli or gaseous microbubbles pass through the ultraq Supported by: Grant from the Vice-Chancellor for Research at Mashhad University of Medical Sciences (NO.439). * Corresponding author. Tel.: +98 511 606 7489; fax: +98 511 842 9828. E-mail address: [email protected] (M.R. Azarpazhooh).
0967-5868/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2008.05.013
sound beam, have also been observed during such monitoring. Giller et al. observed MES in 11 patients during routine TCD studies after aneurysm coiling.4 Brain CT scans revealed hypodense lesions in 82% of the 11 patients with MES, compared with 24% of 123 patients without MES (p < 0.001). This study highlighted the possibility that microembolism might have a role in the development of cerebral ischemia after SAH. Romano et al. monitored 23 patients with aneurysmal SAH.5 MES were detected in 70% of patients and in one-third of all vessels monitored. Although MES were more common among patients with clinical vasospasm (83% vs. 54%), the difference did not reach statistical significance. It is unlikely that angiographic procedures and local brain manipulation or retraction injuries that occur at the time of surgery result in delayed MES. However, it is not clear whether MES originate from the aneurysm sac, endothelial damage due to vasospasm or the structural changes in the vessel wall caused by inflammation. Qureshi et al. suggested that MES might develop within the aneurysmal sac. They detected embolism from the aneurysmal sac in 3.3% of 269 patients.6 In the absence of a cardiac or a carotid artery embolic source, the possible embolic sources in SAH include vasospastic arterial segments, thrombus in an aneurysm sac, atheroma disrupted during clipping or coiling of the aneurysm, presence of a vascular stump arising from vessel
391
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sacrifice, thrombosis after extracranial-intracranial bypass procedures and hypercoaguable states.7 The possibility that microembolism might have a role in cerebral ischemia after SAH has been suggested but remains unproven. This study was designed to define the origin of MES in SAH by comparing aneurysmal and non-aneurysmal SAH and their possible role in cerebral ischemia. 2. Patients and methods From 2005 to 2007 patients with SAH admitted to the neurology and neurosurgery departments at Ghaem Hospital in Mashhad, Iran were investigated in a prospective study. This study was approved by the ethics committee of the Mashhad University of Medical Sciences. Demographic parameters including age and sex, date of SAH, primary neurological deficit, angiographic findings, surgical management and CT scan findings were recorded for each patient. The Fisher scale was used for grading CT scan findings and the Hunt-Hess score for clinical severity.8–10 Exclusion criteria were atrial fibrillation, recent myocardial infarction, valvular heart disease, previous stroke, angiographic evidence of more than 50% internal carotid or middle cerebral artery stenosis, and traumatic SAH. CT scanning was performed as the first imaging test for diagnosis of SAH. Focal neurological deficits due to vasospasm were assessed by thorough neurological examination.11 Symptomatic vasospasm was defined as a focal neurological deficit not due to re-bleeding, hydrocephalus, metabolic abnormalities, or surgical or angiographic complications. Cerebral angiography was performed for diagnosis of aneurysms in all patients. However, angiographic criteria were not used for determination of vasospasm. Patients were divided into two groups: aneurysmal and non-aneurysmal SAH. Angiography was repeated in patients with an initial diagnosis of non-aneurysmal SAH. Patients were also divided into early (within 72 h of SAH onset) and late (after 2 weeks) surgery groups.
TCD evaluation was performed using an Atys TCD ultrasonographic instrument (Atys Medical, St Genislaval, France) equipped with a 2 MHz probe and a Spencer head frame. The patients were monitored 3 times per week during their inpatient stay. Both middle cerebral arteries (MCAs) were monitored every session alternatively. In each monitoring session one experienced operator performed TCD to detect vasospasm and then monitored each MCA for 30 min using the Monolateral Multigate mode to check for MES. The results were reviewed off-line. Ultrasonographic vasospasm in the MCA was defined and graded as described.12,13 MES were defined as being random, unidirectional, P6 dB in intensity, and 6100 ms in duration signals, with an associated characteristic chirping sound.14 The chi-squared (v2) test and Fisher’s exact t-test were used to analyze the relationship between the presence of MES, vasospasm and other demographic factors. All data were analyzed using the Statistical Package for the Social Sciences software (version 11, SPSS, Chicago, IL, USA). 3. Results During the study, 52 patients with SAH were admitted, of whom 27 patients entered the study (Table 1). The average age of the patients (mean ± standard deviation) was 52.07 ± 14.29 years (range 17–80), and there were nearly equal numbers of males and females. About 52% (14/27) were grade 2 on the Fisher CT scale and 56% (15/27) were grade II on the Hunt-Hess clinical scale. Fifteen patients (56%) had aneurysmal and 12 (44%) had non-aneurysmal SAH. Based on angiographic findings, the most common sites of aneurysms were the anterior communicating artery (ACoA) (47%) and MCA (40%). Ten aneurysmal patients (66.6%) underwent surgical management in Ghaem Hospital, one died before surgery and 4 others had surgery in other hospitals. The time of surgery was late in 70% and early in 30% of cases. Overall, there were 4 deaths, all in the aneurysmal SAH group.
Table 1 Clinical data of 27 patients with subarachnoid hemorrhage (SAH). No.
Sex
Age
Hunt-Hess score
Fisher grade
Aneurysm location
Surgery
Vasospasm / time and severity
Symptomatic vasospasm
First MES detection
Result
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
M M F F F M M F F M F M F M F M M F F M F M F M M M F
50 67 57 60 48 72 50 35 37 52 55 62 49 54 55 47 37 44 17 78 66 54 50 47 26 80 57
II V I II II IV III II II I II III II II II II III II IV III I II II II I III II
4 4 2 2 3 2 4 3 2 2 2 3 2 2 3 3 4 2 4 2 2 2 1 2 3 4 2
– – ACoA ACA – Right ACoA – ACoA – MCA – Right – ACoA MCA – Left MCA – Left – MCA – Right – MCA – Right ACoA – – – MCA – Left ACoA – – ACoA Top basilar
– – Early Late – – Late – – – Early Late – – Late – Late Early – – – Late Late – – – –
Day – – Day Day – Day – – Day – Day – Day Day Day Day
3 – Mod –Left / Right
– – – Yes – – Yes – – – – Yes – – –
Day – – Day Day – Day – –
4 – Mild – Left
– – – – Day – – – Day – Day Day – – – – Day – – – – Day Day – – – –
Discharged Discharged Died Discharged Died N/A Died Discharged N/A Discharged Discharged Discharged N/A Discharged N/A Discharged Discharged Discharged N/A Discharged Discharged Discharged Discharged Discharged Discharged Died N/A
6 – Mild – Right 10 – Mild – Left 3 – Moderate – Left
5 – Mild –Left 5 – Mod –Left/Right 5 – Mild – Right 7 – Mild – Right 8 – Mild – Right 12 – Mod – Right
6 – Mod – Left 6 – Mild – Left 11 – Mod –Left / Right
Yes – Yes – – – – – – – –
5
10 5 13
12
6 15
ACA = anterior cerebral artery, ACoA = anterior communicating artery, Hunt-Hess and Fisher score,8–10 MCA = middle cerebral artery, MES = microembolic signals; Mod = moderate, = Nil, N/A = not available. Early surgery was within 72 h of SAH onset and late surgery 2 weeks or more after SAH onset.
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Monitoring was initiated a mean interval of 5.1 days after SAH (range 3–12 days). Vasospasm was detected in 14 patients (52%) beginning on average 6.2 days after SAH (range 3–12 days) and in 17/54 monitored vessels (31.4%) including 3 bilateral cases. The incidence of vasospasm in aneurysmal and non-aneurysmal groups was similar. Symptomatic vasospasm was detected in 5 patients (18.5%). MES were detected in 7/27 patients (26%) but they were observed only in those patients with aneurysmal SAH (7/15, 47%). MES were found in 2/5 patients (40%) with symptomatic vasospasm and 5/22 patients (23%) without. MES were first detected 9.4 days on average after SAH (range 5–15 days). In those patients with MES, the mean number was 1.4 per monitoring session (range 1–3). MES were detected during one monitoring session only in 5 patients and in 2 consecutive monitoring sessions in 2 patients. Bilateral MES were not found in any patients. In the 7 patients with MES recorded from the MCA, 4 had ipsilateral MCA and 3 had ipsilateral ACoA aneurysms. Therefore only 57% of cases with MES had an aneurysm along the monitored vessel. Two of the 3 patients with MES associated with ACoA aneurysms had MCA vasospasm. MES in one patient developed after coiling of the ACoA aneurysm. One MES-positive patient with an MCA aneurysm developed deep vein thrombosis. Statistical analysis showed a significant difference between aneurysmal and non-aneurysmal SAH for the presence of MES (p = 0.007). However, there was no significant relationship between MES and the presence of an aneurysm along the monitored vessel (p = 0.658). There was also no significant relationship between MES and vasospasm (p = 0.224) or symptomatic vasospasm (p = 0.388). Multivariate analysis showed there was also no significant relationship between MES and clinical severity (Hunt-Hess) (p = 0.494), amount and location of bleeding (Fisher) (p = 0.484), age (p = 0.435), gender (p = 0.454) and outcome (p = 0.711).
4. Discussion Although MES have been reported in SAH, it is uncertain where they originate or whether they contribute to brain ischemia.5 The detection of MES provides important pathophysiological information in a variety of disorders, but their clinical importance and possible therapeutic implications are still under debate.7 There are few data on MES frequency in aneurysmal SAH and no published data on MES frequency in non-aneurysmal SAH. In this study, we detected MES in 47% (7/15) of aneurysmal and in 0% (0/12) of nonaneurysmal patients. The origin of MES in SAH is not clearly determined. The possible sites might be vasospastic arterial segments, thrombus in an aneurysmal sac, surgical complications and hypercoaguable states.7 In our study, even though MES were detected only in aneurysmal patients, 3/7 patients with MES did not have an aneurysm along the monitored vessel. Thrombus in an aneurysmal sac might be one source of MES, as first proposed by Qureshi et al.,6 although this does not account for all patients. However, we did not detect MES in any patient without an aneurysm. Although this was not proven in our sample, this lack of MES might be explained by an absence of an aneurysmal sac, or less severe CT scans or clinical gradings that would result in less endothelial disruption, bleeding, vasospasm and surgical procedures. In our study with a relatively small sample size there was no significant relationship between MES and the occurrence of vasospasm or symptomatic vasospasm. However, aneurysmal patients showed more severe vasospasm. It is still possible that vasospastic arterial segments may have a role in MES formation. One patient with an MCA aneurysm without vasospasm developed MES after
surgery, which suggests that surgical intervention has a role in MES formation.4 One patient with an MCA aneurysm and moderate vasospasm developed deep venous thrombosis. In this patient the source of detected MES might have been a hypercoaguable state leading to thrombus formation in any site of the cerebral vasculature, including vasospastic arterial segments or the aneurysmal sac. Hypercoaguability may also be implicated in the patient with MES, an ACoA aneurysm and no vasospasm. The increased susceptibility to thrombus formation after SAH is mainly due to an increased tendency for platelet aggregation.15,16 This phenomenon may be implicated especially in patients with neither vasospasm nor surgical intervention. There were some limitations with our study, in particular the small sample size. We did not include critically ill patients. Our hospital is a referral centre for the region, and our patient population may not be representative of patients treated in other institutions as we have more patients in poor grades. Patients were not monitored after hospital discharge, although this may not be important since delayed ischaemic complications seldom occur after hospital discharge. Further studies with a larger sample size and longer follow-up in SAH patients are recommended. This would clarify the role of MES in the development of neurological and cognitive deficits due to SAH and the possible effectiveness of treatments such as anti-thrombotic therapy. In conclusion, there are several possible factors that might contribute to MES formation in an individual with SAH, including thrombus in an aneurysm sac, vasospasm, surgical intervention and hypercoaguability. Other unknown factors may also be implicated. Therefore, identifying a single factor as the source of MES may not be possible. Acknowledgements The authors thank the neurology and neurosurgery intensive care units of Ghaem Hospital for their support of this study. Dr M.T. Shakeri assisted with data analysis, Mrs Khaniani supported patients during TCD monitoring, Miss Tamara Tamamgar and Miss Sara Velayati helped gather patient data, and Mr M.A. Rasaee provided editorial assistance. This study was funded by a grant from the Vice-Chancellor for Research at Mashhad University of Medical Sciences (#439). The project was presented as an M.D. thesis by Dr Arash Velayati. References 1. Fisher CM, Roberson GH, Ojemann RG. Cerebral vasospasm with ruptured saccular aneurysm: The clinical manifestations. Neurosurgery 1997;1:245–8. 2. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 1980;6:1–9. 3. Suzuki S, Kimura M, Souma M, et al. Cerebral microthrombosis in symptomatic cerebral vasospasm: A quantitative histological study in autopsy cases. Neurol Med Chir (Tokyo) 1990;30:309–16. 4. Giller CA, Giller AM, Landreneau F. Detection of emboli after surgery for intracerebral aneurysms. Neurosurgery 1998;42:490–3. 5. Romano JG, Forteza AM, Concha M, et al. Detection of microemboli by transcranial doppler ultrasonography in aneurysmal subarachnoid hemorrhage. Neurosurgery 2002;50:1026–30. 6. Qureshi AI, Mohammad Y, Yahia AM, et al. Ischemic events associated with intracranial aneurysms: Multicenter clinical study and review of the literature. Neurosurgery 2000;46:282–9. 7. Azarpazhooh MR, Chambers BR. Clinical application of transcranial Doppler monitoring for embolic signals. J Clin Neurosci 2006;13:799–810. 8. Nazli J, Mayer S. Cerebral vasospasm after subarachnoid hemorrhage. Curr Opin Crit Care 2003;9:113–9. 9. Nikas D. The neurologic system. In: Alspach J, editor. AACN Core Curriculum for Critical Care Nursing. 5th ed. Philadelphia: Saunders; 1998. p. 348. 10. Wojner A. Neurovascular disease. In: Kinney M, Dunbar S, Brooks-Brunn J, et al., editors. AACN Clinical Reference for Critical Care Nursing. 4th ed. St Louis, MO: Mosby; 1998. p. 737–59. 11. Lyden PD, Hantson L. Assessment scales for evaluation of stroke patients. J Stroke Cerebrovasc Dis 1998;7:113–27.
M.R. Azarpazhooh et al. / Journal of Clinical Neuroscience 16 (2009) 390–393 12. Lindegaard KF, Nornes H, Bakke SJ, et al. Cerebral vasospasm diagnosis by means of angiography and blood velocity measurements. Acta Neurochir (Wien) 1989;100:12–24. 13. Newell DW, Grady MS, Eskridge JM, et al. Distribution of angiographic vasospasm after subarachnoid hemorrhage: Implications for diagnosis by transcranial Doppler ultrasonography. Neurosurgery 1990;27:574–7. 14. Basic identification criteria of Doppler microembolic signals. Consensus Committee of the Ninth International Cerebral Hemodynamic Symposium. Stroke 1995;26:1123.
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15. Juvela S, Hillbom M, Kaste M. Platelet thromboxane release and delayed cerebral ischemia in patients with subarachnoid hemorrhage. J Neurosurg 1991;74:386–92. 16. Ohkuma H, Ogane K, Fujita S, et al. Impairment of anti-platelet–aggregating activity of endothelial cells after experimental subarachnoid hemorrhage. Stroke 1993;24:1541–6.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Microembolic signals in subarachnoid hemorrhage q Mahmoud Reza Azarpazhooh a,*, Arash Velayati b, Brian R. Chambers c, Hossain Mashhadi Nejad d, Payam Sasan Nejad a a
Department of Neurology, Ghaem Medical Center, Mashhad University of Medical Science (MUMS), Taghi Abad Square, Mashhad 9196773117, Iran Division of Human Genetics, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran c Austin Health, National Stroke Research Institute, University of Melbourne, Heidelberg Repatriation Hospital, Heidelberg Heights, Victoria, Australia d Department of Neurosurgery, Ghaem Medical Center, Mashhad University of Medical Science, Mashhad, Iran b
a r t i c l e
i n f o
Article history: Received 16 February 2008 Accepted 19 May 2008
Keywords: Subarachnoid hemorrhage Microembolic signals Vasospasm
a b s t r a c t Microembolic signals (MES) detected by transcranial Doppler (TCD) have been reported in subarachnoid hemorrhage (SAH), although their origin and contribution to brain ischemia remain uncertain. We conducted a prospective study to evaluate the frequency of MES among patients with SAH and to determine their origin. Twenty-seven patients with SAH, comprising 15 aneurysmal and 12 non-aneurysmal patients, participated in the study. TCD evaluation was performed using a 2 MHz probe. Patients were studied three times per week during their in-patient stay to detect vasospasm, and then each middle cerebral artery (MCA) was monitored for 30 min using the Monolateral Multigate mode to detect MES. Using this method, MES were detected in 7 out of 15 patients (47%) with aneurysmal SAH and were not seen in non-aneurysmal patients (p = 0.007). Vasospasm occurred in 52% (14/27) of cases. However, clinical signs and symptoms of vasospasm were identified in only 18.5% (5/27). There was no significant relationship between MES and vasospasm (p = 0.224). Also, no relationship was found between MES and the location of the aneurysm (p = 0.685). Thus, in this study MES were only detected in aneurysmal SAH. However, we did not find a relationship between the location of the aneurysm and MES, or the presence of vasospasm and MES. Therefore, MES in patients with SAH may also originate from vascular pathology other than the aneurysm sac or vascular spasm. Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction Subarachnoid hemorrhage (SAH) is a serious form of stroke, with high morbidity and mortality largely attributable to the initial bleed, rebleeding, and vasospasm.1,2 The pathogenesis of cerebral vasospasm after SAH is not fully understood, but inflammatory responses and immunological reactions have been implicated.2 In a study of the brains of SAH patients who died shortly after the development of vasospasm, histological examination revealed white fibrin microthrombi associated with infarction in the territory of vasospastic arteries, corresponding to hypodensities on brain CT scans and neurological findings.3 The study proposed that damage to the endothelial wall from vasospasm might induce microthrombosis and embolism. Transcranial Doppler (TCD) is used routinely in some centres to monitor SAH patients for vasospasm. Microembolic signals (MES), which are brief, high-intensity transients that occur when particulate microemboli or gaseous microbubbles pass through the ultraq Supported by: Grant from the Vice-Chancellor for Research at Mashhad University of Medical Sciences (NO.439). * Corresponding author. Tel.: +98 511 606 7489; fax: +98 511 842 9828. E-mail address: [email protected] (M.R. Azarpazhooh).
0967-5868/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2008.05.013
sound beam, have also been observed during such monitoring. Giller et al. observed MES in 11 patients during routine TCD studies after aneurysm coiling.4 Brain CT scans revealed hypodense lesions in 82% of the 11 patients with MES, compared with 24% of 123 patients without MES (p < 0.001). This study highlighted the possibility that microembolism might have a role in the development of cerebral ischemia after SAH. Romano et al. monitored 23 patients with aneurysmal SAH.5 MES were detected in 70% of patients and in one-third of all vessels monitored. Although MES were more common among patients with clinical vasospasm (83% vs. 54%), the difference did not reach statistical significance. It is unlikely that angiographic procedures and local brain manipulation or retraction injuries that occur at the time of surgery result in delayed MES. However, it is not clear whether MES originate from the aneurysm sac, endothelial damage due to vasospasm or the structural changes in the vessel wall caused by inflammation. Qureshi et al. suggested that MES might develop within the aneurysmal sac. They detected embolism from the aneurysmal sac in 3.3% of 269 patients.6 In the absence of a cardiac or a carotid artery embolic source, the possible embolic sources in SAH include vasospastic arterial segments, thrombus in an aneurysm sac, atheroma disrupted during clipping or coiling of the aneurysm, presence of a vascular stump arising from vessel
391
M.R. Azarpazhooh et al. / Journal of Clinical Neuroscience 16 (2009) 390–393
sacrifice, thrombosis after extracranial-intracranial bypass procedures and hypercoaguable states.7 The possibility that microembolism might have a role in cerebral ischemia after SAH has been suggested but remains unproven. This study was designed to define the origin of MES in SAH by comparing aneurysmal and non-aneurysmal SAH and their possible role in cerebral ischemia. 2. Patients and methods From 2005 to 2007 patients with SAH admitted to the neurology and neurosurgery departments at Ghaem Hospital in Mashhad, Iran were investigated in a prospective study. This study was approved by the ethics committee of the Mashhad University of Medical Sciences. Demographic parameters including age and sex, date of SAH, primary neurological deficit, angiographic findings, surgical management and CT scan findings were recorded for each patient. The Fisher scale was used for grading CT scan findings and the Hunt-Hess score for clinical severity.8–10 Exclusion criteria were atrial fibrillation, recent myocardial infarction, valvular heart disease, previous stroke, angiographic evidence of more than 50% internal carotid or middle cerebral artery stenosis, and traumatic SAH. CT scanning was performed as the first imaging test for diagnosis of SAH. Focal neurological deficits due to vasospasm were assessed by thorough neurological examination.11 Symptomatic vasospasm was defined as a focal neurological deficit not due to re-bleeding, hydrocephalus, metabolic abnormalities, or surgical or angiographic complications. Cerebral angiography was performed for diagnosis of aneurysms in all patients. However, angiographic criteria were not used for determination of vasospasm. Patients were divided into two groups: aneurysmal and non-aneurysmal SAH. Angiography was repeated in patients with an initial diagnosis of non-aneurysmal SAH. Patients were also divided into early (within 72 h of SAH onset) and late (after 2 weeks) surgery groups.
TCD evaluation was performed using an Atys TCD ultrasonographic instrument (Atys Medical, St Genislaval, France) equipped with a 2 MHz probe and a Spencer head frame. The patients were monitored 3 times per week during their inpatient stay. Both middle cerebral arteries (MCAs) were monitored every session alternatively. In each monitoring session one experienced operator performed TCD to detect vasospasm and then monitored each MCA for 30 min using the Monolateral Multigate mode to check for MES. The results were reviewed off-line. Ultrasonographic vasospasm in the MCA was defined and graded as described.12,13 MES were defined as being random, unidirectional, P6 dB in intensity, and 6100 ms in duration signals, with an associated characteristic chirping sound.14 The chi-squared (v2) test and Fisher’s exact t-test were used to analyze the relationship between the presence of MES, vasospasm and other demographic factors. All data were analyzed using the Statistical Package for the Social Sciences software (version 11, SPSS, Chicago, IL, USA). 3. Results During the study, 52 patients with SAH were admitted, of whom 27 patients entered the study (Table 1). The average age of the patients (mean ± standard deviation) was 52.07 ± 14.29 years (range 17–80), and there were nearly equal numbers of males and females. About 52% (14/27) were grade 2 on the Fisher CT scale and 56% (15/27) were grade II on the Hunt-Hess clinical scale. Fifteen patients (56%) had aneurysmal and 12 (44%) had non-aneurysmal SAH. Based on angiographic findings, the most common sites of aneurysms were the anterior communicating artery (ACoA) (47%) and MCA (40%). Ten aneurysmal patients (66.6%) underwent surgical management in Ghaem Hospital, one died before surgery and 4 others had surgery in other hospitals. The time of surgery was late in 70% and early in 30% of cases. Overall, there were 4 deaths, all in the aneurysmal SAH group.
Table 1 Clinical data of 27 patients with subarachnoid hemorrhage (SAH). No.
Sex
Age
Hunt-Hess score
Fisher grade
Aneurysm location
Surgery
Vasospasm / time and severity
Symptomatic vasospasm
First MES detection
Result
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
M M F F F M M F F M F M F M F M M F F M F M F M M M F
50 67 57 60 48 72 50 35 37 52 55 62 49 54 55 47 37 44 17 78 66 54 50 47 26 80 57
II V I II II IV III II II I II III II II II II III II IV III I II II II I III II
4 4 2 2 3 2 4 3 2 2 2 3 2 2 3 3 4 2 4 2 2 2 1 2 3 4 2
– – ACoA ACA – Right ACoA – ACoA – MCA – Right – ACoA MCA – Left MCA – Left – MCA – Right – MCA – Right ACoA – – – MCA – Left ACoA – – ACoA Top basilar
– – Early Late – – Late – – – Early Late – – Late – Late Early – – – Late Late – – – –
Day – – Day Day – Day – – Day – Day – Day Day Day Day
3 – Mod –Left / Right
– – – Yes – – Yes – – – – Yes – – –
Day – – Day Day – Day – –
4 – Mild – Left
– – – – Day – – – Day – Day Day – – – – Day – – – – Day Day – – – –
Discharged Discharged Died Discharged Died N/A Died Discharged N/A Discharged Discharged Discharged N/A Discharged N/A Discharged Discharged Discharged N/A Discharged Discharged Discharged Discharged Discharged Discharged Died N/A
6 – Mild – Right 10 – Mild – Left 3 – Moderate – Left
5 – Mild –Left 5 – Mod –Left/Right 5 – Mild – Right 7 – Mild – Right 8 – Mild – Right 12 – Mod – Right
6 – Mod – Left 6 – Mild – Left 11 – Mod –Left / Right
Yes – Yes – – – – – – – –
5
10 5 13
12
6 15
ACA = anterior cerebral artery, ACoA = anterior communicating artery, Hunt-Hess and Fisher score,8–10 MCA = middle cerebral artery, MES = microembolic signals; Mod = moderate, = Nil, N/A = not available. Early surgery was within 72 h of SAH onset and late surgery 2 weeks or more after SAH onset.
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Monitoring was initiated a mean interval of 5.1 days after SAH (range 3–12 days). Vasospasm was detected in 14 patients (52%) beginning on average 6.2 days after SAH (range 3–12 days) and in 17/54 monitored vessels (31.4%) including 3 bilateral cases. The incidence of vasospasm in aneurysmal and non-aneurysmal groups was similar. Symptomatic vasospasm was detected in 5 patients (18.5%). MES were detected in 7/27 patients (26%) but they were observed only in those patients with aneurysmal SAH (7/15, 47%). MES were found in 2/5 patients (40%) with symptomatic vasospasm and 5/22 patients (23%) without. MES were first detected 9.4 days on average after SAH (range 5–15 days). In those patients with MES, the mean number was 1.4 per monitoring session (range 1–3). MES were detected during one monitoring session only in 5 patients and in 2 consecutive monitoring sessions in 2 patients. Bilateral MES were not found in any patients. In the 7 patients with MES recorded from the MCA, 4 had ipsilateral MCA and 3 had ipsilateral ACoA aneurysms. Therefore only 57% of cases with MES had an aneurysm along the monitored vessel. Two of the 3 patients with MES associated with ACoA aneurysms had MCA vasospasm. MES in one patient developed after coiling of the ACoA aneurysm. One MES-positive patient with an MCA aneurysm developed deep vein thrombosis. Statistical analysis showed a significant difference between aneurysmal and non-aneurysmal SAH for the presence of MES (p = 0.007). However, there was no significant relationship between MES and the presence of an aneurysm along the monitored vessel (p = 0.658). There was also no significant relationship between MES and vasospasm (p = 0.224) or symptomatic vasospasm (p = 0.388). Multivariate analysis showed there was also no significant relationship between MES and clinical severity (Hunt-Hess) (p = 0.494), amount and location of bleeding (Fisher) (p = 0.484), age (p = 0.435), gender (p = 0.454) and outcome (p = 0.711).
4. Discussion Although MES have been reported in SAH, it is uncertain where they originate or whether they contribute to brain ischemia.5 The detection of MES provides important pathophysiological information in a variety of disorders, but their clinical importance and possible therapeutic implications are still under debate.7 There are few data on MES frequency in aneurysmal SAH and no published data on MES frequency in non-aneurysmal SAH. In this study, we detected MES in 47% (7/15) of aneurysmal and in 0% (0/12) of nonaneurysmal patients. The origin of MES in SAH is not clearly determined. The possible sites might be vasospastic arterial segments, thrombus in an aneurysmal sac, surgical complications and hypercoaguable states.7 In our study, even though MES were detected only in aneurysmal patients, 3/7 patients with MES did not have an aneurysm along the monitored vessel. Thrombus in an aneurysmal sac might be one source of MES, as first proposed by Qureshi et al.,6 although this does not account for all patients. However, we did not detect MES in any patient without an aneurysm. Although this was not proven in our sample, this lack of MES might be explained by an absence of an aneurysmal sac, or less severe CT scans or clinical gradings that would result in less endothelial disruption, bleeding, vasospasm and surgical procedures. In our study with a relatively small sample size there was no significant relationship between MES and the occurrence of vasospasm or symptomatic vasospasm. However, aneurysmal patients showed more severe vasospasm. It is still possible that vasospastic arterial segments may have a role in MES formation. One patient with an MCA aneurysm without vasospasm developed MES after
surgery, which suggests that surgical intervention has a role in MES formation.4 One patient with an MCA aneurysm and moderate vasospasm developed deep venous thrombosis. In this patient the source of detected MES might have been a hypercoaguable state leading to thrombus formation in any site of the cerebral vasculature, including vasospastic arterial segments or the aneurysmal sac. Hypercoaguability may also be implicated in the patient with MES, an ACoA aneurysm and no vasospasm. The increased susceptibility to thrombus formation after SAH is mainly due to an increased tendency for platelet aggregation.15,16 This phenomenon may be implicated especially in patients with neither vasospasm nor surgical intervention. There were some limitations with our study, in particular the small sample size. We did not include critically ill patients. Our hospital is a referral centre for the region, and our patient population may not be representative of patients treated in other institutions as we have more patients in poor grades. Patients were not monitored after hospital discharge, although this may not be important since delayed ischaemic complications seldom occur after hospital discharge. Further studies with a larger sample size and longer follow-up in SAH patients are recommended. This would clarify the role of MES in the development of neurological and cognitive deficits due to SAH and the possible effectiveness of treatments such as anti-thrombotic therapy. In conclusion, there are several possible factors that might contribute to MES formation in an individual with SAH, including thrombus in an aneurysm sac, vasospasm, surgical intervention and hypercoaguability. Other unknown factors may also be implicated. Therefore, identifying a single factor as the source of MES may not be possible. Acknowledgements The authors thank the neurology and neurosurgery intensive care units of Ghaem Hospital for their support of this study. Dr M.T. Shakeri assisted with data analysis, Mrs Khaniani supported patients during TCD monitoring, Miss Tamara Tamamgar and Miss Sara Velayati helped gather patient data, and Mr M.A. Rasaee provided editorial assistance. This study was funded by a grant from the Vice-Chancellor for Research at Mashhad University of Medical Sciences (#439). The project was presented as an M.D. thesis by Dr Arash Velayati. References 1. Fisher CM, Roberson GH, Ojemann RG. Cerebral vasospasm with ruptured saccular aneurysm: The clinical manifestations. Neurosurgery 1997;1:245–8. 2. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 1980;6:1–9. 3. Suzuki S, Kimura M, Souma M, et al. Cerebral microthrombosis in symptomatic cerebral vasospasm: A quantitative histological study in autopsy cases. Neurol Med Chir (Tokyo) 1990;30:309–16. 4. Giller CA, Giller AM, Landreneau F. Detection of emboli after surgery for intracerebral aneurysms. Neurosurgery 1998;42:490–3. 5. Romano JG, Forteza AM, Concha M, et al. Detection of microemboli by transcranial doppler ultrasonography in aneurysmal subarachnoid hemorrhage. Neurosurgery 2002;50:1026–30. 6. Qureshi AI, Mohammad Y, Yahia AM, et al. Ischemic events associated with intracranial aneurysms: Multicenter clinical study and review of the literature. Neurosurgery 2000;46:282–9. 7. Azarpazhooh MR, Chambers BR. Clinical application of transcranial Doppler monitoring for embolic signals. J Clin Neurosci 2006;13:799–810. 8. Nazli J, Mayer S. Cerebral vasospasm after subarachnoid hemorrhage. Curr Opin Crit Care 2003;9:113–9. 9. Nikas D. The neurologic system. In: Alspach J, editor. AACN Core Curriculum for Critical Care Nursing. 5th ed. Philadelphia: Saunders; 1998. p. 348. 10. Wojner A. Neurovascular disease. In: Kinney M, Dunbar S, Brooks-Brunn J, et al., editors. AACN Clinical Reference for Critical Care Nursing. 4th ed. St Louis, MO: Mosby; 1998. p. 737–59. 11. Lyden PD, Hantson L. Assessment scales for evaluation of stroke patients. J Stroke Cerebrovasc Dis 1998;7:113–27.
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