- Email: [email protected]
Assessment of cerebrovascular reserve capacity in asymptomatic and symptomatic hemodynamically significant carotid stenoses and occlusions
Assessment of Cerebrovascular Reserve Capacity in Asymptomatic and Symptomatic Hemodynamically Significant Carotid Stenoses and Occlusions La´szlo´ Orosz, M.D.,* Be´la Fu ¨ lesdi, M.D., Ph.D.,*† Arjan Hoksbergen, M.D.,㛳 Georgios Settakis, M.D.,‡ Jo´zsef Kolla´r, M.D., Ph.D.,§ Martien Limburg, M.D., Ph.D.,** and Gyo ¨ rgy Cse´csei, M.D., Ph.D.¶ *Department of Surgery, †Anesthesiology and Intensive Care, ‡Neurology, §Neurosurgery, ¶Radiology, University of Debrecen, Health and Science Center, Debrecen, Hungary, and 储Department of Vascular Surgery, **Biostatistics, Academic Medical Center, Amsterdam, The Netherlands
Orosz L, Fu ¨ lesdi B, Hoksbergen A, Settakis G, Kolla´r J, Limburg M, Cse´csei G. Assessment of cerebrovascular reserve capacity in asymptomatic and symptomatic hemodynamically significant carotid stenoses and occlusions. Surg Neurol 2002;57:333–339. BACKGROUND
Cerebrovascular reactivity measurements are believed to be a helpful tool for selecting patients who are at higher risk for hemodynamic strokes. The aim of this study was to compare cerebral vasoreactivity among patients suffering from internal carotid artery stenosis of different severity (asymptomatic stenosis, asymptomatic occlusion, symptomatic stenosis, symptomatic occlusion). METHODS
Sixty-two patients with asymptomatic and symptomatic internal carotid artery stenoses and occlusions underwent transcranial Doppler-acetazolamide tests. Absolute velocities of the middle cerebral arteries (MCAV), percent increases of the MCAV at different time points of the test (cerebrovascular reactivity, CVR) and maximal percent increase after administration of acetazolamide (cerebrovascular reserve, CRC) were compared on the affected and non-affected sides. Asymmetry indices (CRC affected side/CRC non-affected side) were compared between the groups of different severity of obstructive lesion. RESULTS
Resting MCAV was similar on both sides in all groups. A significant side-difference of the MCAV values after acetazolamide was observed only in the symptomatic groups. Difference of cerebrovascular reserve capacity between the affected and non-affected side was statistically signif-
Address reprint requests to: Dr Be´la Fu ¨ lesdi, Department of Anesthesiology and Intensive Care, University of Debrecen, Health and Science Center H-4012 Debrecen, Hungary. Received February 14, 2001; accepted November 28, 2001. © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
icant only in the symptomatic groups (CRC symptomatic stenosis 36.6 ⫾ 20.9% vs. 71.1 ⫾ 27.9%, CRC symptomatic occlusion: 31.2 ⫾ 24.6% vs. 64.5 ⫾ 29.7%). Asymmetry index of the CRC was near to 1 in the asymptomatic stenosis group only, while in all the other groups this index referred to a significant hemispheric asymmetry of the vasoreactivity. CONCLUSIONS
Although in general cerebrovascular reserve capacity is compromised in cases of hemodynamically significant carotid lesions, there is a large individual variability within the subgroups. Further randomized studies are needed to clarify whether the clinical efficiency of carotid endarterectomy and extra-intracranial bypass may be improved by selecting the patients using hemodynamic criteria. © 2002 by Elsevier Science Inc. KEY WORDS
Carotid artery stenosis, transcranial Doppler, cerebrovascular reactivity and reserve capacity, acetazolamide.
he role of carotid stenosis in ischemic cerebrovascular diseases has already been known for more than 100 years. Since the first endarterectomy performed by Carrera in 1951, carotid surgery procedures have taken flight. At first the efficacy of extra-intracranial bypass was tested to clarify whether it is superior for preventing ipsilateral strokes compared to conservative therapy. Although the EC-IC Bypass Study Group [1] published a negative result, recent data suggest that in a selected group of patients extra-intracranial bypass may improve the patient’s condition [2–5]. A hemo-
T
0090-3019/02/$–see front matter PII S0090-3019(02)00689-4
334 Surg Neurol 2002;57:333–339
dynamically significant carotid stenosis is proposed to be operated, as was proven by both the ECAS and NASCET trials [6,7]. Although the ACAS trial also showed a beneficial effect of carotid endarterectomy in cases of asymptomatic carotid stenosis, the efficacy of the procedure is still debated, as 83 patients have to be operated on to prevent 1 stroke within 2 years of follow-up [8]. Therefore, recently a more strict patient selection was suggested in cases of asymptomatic carotid stenosis for carotid endarterectomies. The term “more strict patient selection” in the groups of carotid occlusions and asymptomatic stenoses is meant as differentiation of patients who are at higher risk for hemodynamic stroke from those who are at higher risk from embolic stroke. Previous observations suggest that a stroke caused by a hemodynamically significant carotid stenosis or occlusion is in 2/3 of the cases embolic and in 1/3 of the cases hemodynamic in origin [9]. It seems to be logical that a cerebral revascularisation procedure (EC-IC bypass or endarterectomy) has different rates of efficacy in preventing strokes in the two different pathogenetical groups. Besides the assessment of the collateral capacity of cerebral circulation, cerebral vasoreactivity testing has also been used for evaluating patients who have compromised cerebral hemodynamics and, therefore, may be candidates for revascularisation procedures. Carbon dioxide inhalation [10], breath holding test, and acetazolamide have been used for this purpose [11,12]. All these stimuli induce vasodilation of the brain arterioles, resulting in an increase of the cerebral blood flow (CBF). This CBF increase is less if cerebral hemodynamics are compromised and can be diagnosed by different methods, such as SPECT, PET, MR angiography, and transcranial Doppler sonography. In the recent decade, acetazolamide was the most frequently used vasodilatory stimulus for this purpose. So far, the majority of authors have selected groups of patients (asymptomatic or symptomatic stenoses, carotid occlusions), but only a few of them compared cerebral vasoreactivity in patients having different degrees of carotid obstruction. Therefore, in the present study, we wanted to compare cerebrovascular reserve capacity as measured after administration of acetazolamide in patients with symptomatic and asymptomatic carotid stenoses and occlusions. The main goal of the study was to clarify whether there is a difference between the cerebral vasoreactivity in these four different carotid obstructive lesions.
Orosz et al
Patients and Methods Patients were recruited from the Department of Neurology and Neurosurgery at the University of Debrecen Health and Science Center, and from the Department of Vascular Surgery, Academic Medical Center Amsterdam. Asymptomatic carotid stenoses and occlusions were occasionally found through regular ultrasound screening of the carotid arteries before operations for peripheral arterial diseases or open-heart surgery. A patient suffering from carotid artery stenosis or occlusion was considered to be asymptomatic, if there was no amaurosis fugax or neurological symptoms in the previous medical history present and brain computed tomography (CT) scan showed a normal result. Patients with symptomatic stenosis and occlusion were inpatients in the Department of Neurology, University of Debrecen, treated in the Stroke Unit; in these patients either a transient or a permanent neurological deficit could be observed and/or the brain CT showed infarctions. Carotid stenoses and occlusions were diagnosed by the 10 MHz probe of the Hewlett-Packard Sonos 2000 (USA) equipment. Both longitudinal and transverse images were performed. For measuring the severity of the stenosis on the B-mode image, the NASCET criteria were used [7]. After assessing the carotid arteries, transcranial Doppler measurement of the middle cerebral artery was performed on both sides using EME TC 64 B transcranial Doppler sonograph. The vessel was insonated at 50 mm depth. Resting cerebral blood flow velocity measurements were followed by an i.v. administration of 1g of acetazolamide (Diamox, Lederle Parenterals, Puerto Rico). Blood flow velocity measurements were repeated at 10 and 15 minutes after administration of this vasodilatory stimulus. Systolic, diastolic, and mean blood flow velocities, as well as pulsatility indices were registered in every case. For statistical evaluation only mean blood flow velocities were taken into account. Cerebrovascular reactivity was calculated as the percent increase of the mean blood flow velocity after administration of the vasodilatory stimulus according to the following formula:
CVRC ⫽ 100 ⫻ 共MCAVAZ ⫺ MCAVREST) /MCAVREST where MCAVAZ indicates middle cerebral artery mean blood flow velocity after administration of acetazolamide and MCAVREST indicates the resting value of the middle cerebral artery mean blood flow velocity. Similarly, cerebrovascular reserve capacity (CRC) was defined as the maximal percent increase of the blood flow velocity after administra-
Cerebrocascular Reactivity in Carotid Stenosis and Occlusion
1
Surg Neurol 335 2002;57:333–339
Comparison of Middle Cerebral Artery Mean Blood Flow Velocity Values (in cm/s) at Rest and After Injecting Acetazolamide. Means and Standard Deviations
TIME
AFTER ACETAZOLAMIDE (MIN)
0 10 15 0 10 15 0 10 15 0 10 15
AFFECTED (STENOTIC-OCCLUSIVE)
NON-AFFECTED
SIDE
SIDE
P-VALUE
57.6 ⫾ 11.4 86.1 ⫾ 23.0 91.0 ⫾ 23.0
0.84 0.56 0.27
54.6 ⫾ 9.8 79.4 ⫾ 19.2 82.3 ⫾ 19.6
0.18 0.67 0.65
50.1 ⫾ 11.2 78.6 ⫾ 20.4 81.6 ⫾ 18.8
0.11 0.005 0.002
54.2 ⫾ 16.1 84.2 ⫾ 23.5 86.0 ⫾ 24.6
0.79 0.07 0.04
ASYMPTOMATIC OCCLUSION 58.6 ⫾ 16.1 81.3 ⫾ 23.7 81.1 ⫾ 26.6 ASYMPTOMATIC STENOSIS 48.1 ⫾ 16.6 76.4 ⫾ 20.8 79.1 ⫾ 20.9 SYMPTOMATIC STENOSIS (N ⫽ 15) 43.3 ⫾ 11.3 57.0 ⫾ 19.0 57.1 ⫾ 18.5 SYMPTOMATIC OCCLUSION (N ⫽ 15) 55.2 ⫾ 16.2 68.4 ⫾ 23.3 67.4 ⫾ 22.5
tering the vasodilatory stimulus and was calculated as follows:
CRC ⫽ 100 ⫻ 共MCAVAZMAZ ⫺ MCAVREST)/MCAVREST where MCAVAZMAX indicates the maximal increase of the mean blood flow velocity after acetazolamide. The asymmetry index of the cerebrovascular reserve capacity was calculated by dividing CRC on the affected side by CRC on the non-affected side. Statistical evaluation: Means and standard deviations are reported for all values. Parameters with normal distribution were compared with the appropriate t tests. In case of multiple comparisons, Bonferroni corrections were performed. For nonparametric analysis X2 test was used. A p value of ⬍0.05 was accepted as statistically significant. Statistica99 version 5.5 for Windows (StatSoft, Tulsa, Oklahoma) was used for data analysis.
Results Sixty-two patients (42 males and 20 females, mean age: 63.2 ⫾ 9.6 years, ranges: 42– 81 years) suffering from hemodynamically significant stenosis or occlusion of the internal cerebral artery were entered in the study. There were 16 asymptomatic occlusions, 15 symptomatic occlusions, 16 asymptomatic stenoses, and 15 symptomatic stenoses. The distribution of the symptomatic patients according to their stroke subtypes was as follows: in the occlusion group there were 4 TIAs, 1 RIND, 1 minor stroke, 4 progressing, and 4 completed strokes, while in the stenotic group these numbers were
4-2-7-1-0, respectively. The frequency of TIAs, RIND, and progressing strokes did not differ between the two groups, while in the symptomatic occlusion group minor strokes were less frequent (p ⫽ 0.0132, 2 test) and more completed strokes were observed (p ⫽ 0.031, 2 test). Cerebral blood flow velocities in the middle cerebral arteries: Table 1 summarizes mean blood flow velocities of the MCA (MCAV) at rest and after administering acetazolamide. It is obvious from the data that resting cerebral blood flow velocities as measured in the affected and non-affected side were similar in all groups; no side asymmetry was observed. MCAVs did not differ between the two sides after administration of acetazolamide in the asymptomatic groups. In case of symptomatic stenosis, a marked side difference of the MCAV could be observed after administration of acetazolamide, while in symptomatic occlusions this difference was pronounced only 15 minutes after administering the vasodilatory stimulus. Cerebrovascular reactivity and reserve capacity measurements: Calculated cerebrovascular reactivity and reserve capacity values are summarized in Table 2. The percent increase of the MCAV in the asymptomatic groups was similar on both sides at any time after injecting acetazolamide. The same was true for the maximal percent increase of the blood flow velocities (cerebrovascular reserve capacity, CRC). In symptomatic patients, a decreased vasodilatory ability of the cerebral arterioles was detected ipsilateral to the stenotic-occlusive lesion, which was confirmed by lower cerebrovascular re-
336 Surg Neurol 2002;57:333–339
2
Orosz et al
Comparison of Cerebrovascular Reactivity and Reserve Capacity Values in the Different Groups. Values are Shown as Means and Standard Deviations
TIME
AFTER ACETAZOLAMIDE (MIN)
10 15 CRC 10 15 CRC 10 15 CRC 10 15 CRC
AFFECTED (STENOTIC-OCCLUSIVE)
NON-AFFECTED
SIDE
SIDE
ASYMPTOMATIC OCCLUSION 47.1 ⫾ 40.3 48.3 ⫾ 28.4 40.2 ⫾ 30.2 60.0 ⫾ 39.0 45.5 ⫾ 37.4 64.3 ⫾ 34.8 ASYMPTOMATIC STENOSIS 63.6 ⫾ 41.8 45.9 ⫾ 16.7 69.2 ⫾ 39.6 35.9 ⫾ 25.2 70.8 ⫾ 40.3 60.0 ⫾ 20.2 SYMPTOMATIC STENOSIS (N ⫽ 15) 30.9 ⫾ 20.7 59.9 ⫾ 26.7 31.2 ⫾ 20.2 65.7 ⫾ 30.5 36.6 ⫾ 20.9 71.1 ⫾ 27.9 SYMPTOMATIC OCCLUSION (N ⫽ 15) 30.2 ⫾ 24.6 56.4 ⫾ 26.3 31.7 ⫾ 23.5 59.7 ⫾ 28.7 31.2 ⫾ 24.6 64.5 ⫾ 29.7
activity and reserve capacity values on the affected side. Asymmetry index of cerebrovascular reserve capacity: As mentioned in the methods section, the asymmetry index was calculated by dividing CRC of the affected side by that of the non-affected side. Thus, an asymmetry index less than 1 indicates a lower maximal vasodilatory capacity of the middle cerebral artery territory ipsilateral to the stenoticocclusive lesion, whereas an asymmetry index of
1
P-VALUE
0.92 0.157 0.15 0.12 0.26 0.34 0.002 0.001 0.0006 0.004 0.002 0.003
higher than 1 refers to a more pronounced percent increase of the MCAV contralaterally. The calculated asymmetry indices of the cerebrovascular reserve capacities are shown in Figure 1. Although there is a tendency for all stenotic-occlusive lesions but asymptomatic stenosis to have near 0.5 values, indicating lesser maximal vasodilatory capacity ipsilateral to the lesion, very obviously, these indices show high standard deviation values. Thus, there should be a wide variation of patients ranging from
Asymmetry index of the cerebrovascular reserve capacity calculated by dividing values of the stenotic-occlusive by that of the non-stenotic side. “SY” indicates symptomatic, “ASY” indicates asymptomatic.
Cerebrocascular Reactivity in Carotid Stenosis and Occlusion
a low asymmetry index to greater than one. This observation is also supported by the minimal and maximal values of this index (asymptomatic stenosis: 0.4 –2.92, symptomatic stenosis 0.21–1.29, asymptomatic occlusion ⫺0.97–1.43, symptomatic occlusion ⫺0.17–3.06), indicating that there is a wide individual variation of cerebrovascular reserve capacity. If one takes median values into account, asymptomatic stenosis patients have an index of 1.17, which is near to the expected 1, while all the other patients suffering from stenoses or occlusions have lower medians for asymmetry indices (symptomatic stenosis 0.43, symptomatic occlusions 0.51 and asymptomatic occlusions 0.67), indicating that there is a lower cerebral vasoreactivity ipsilateral to the stenotic-occlusive lesion than on the non-affected side.
Discussion We investigated cerebral blood flow velocities and cerebrovascular reserve capacity values in patients suffering from asymptomatic and symptomatic internal carotid artery stenosis and occlusion. We found that resting blood flow velocities are comparable in the affected and non-affected hemispheres in all groups, but cerebrovascular reserve capacity is of lower magnitude on the affected side than the non-affected one in all groups but asymptomatic stenosis. Classification of the patients into subgroups of asymptomatic and symptomatic lesions revealed the most important question at the beginning of the study. A very detailed questionnaire of the previous medical history (including dysesthesias, temporary or permanent weakness of the extremities, speech disturbances, visual symptoms) alone was considered to be uncertain. In our opinion, in some cases temporary circulatory disturbances may be mild and short so the patient does not remember them any more. Therefore, beside clinical criteria we also introduced morphological criteria for patient selection and only patients with negative CT scans and negative medical history of stroke were classified to the asymptomatic group. Another methodological point was the use of transcranial Doppler and acetazolamide as a vasodilatory stimulus. Acetazolamide is a widely accepted stimulus for cerebral hemodynamic studies [13–19]. The drug acts by inhibiting the enzyme carbonic anhydrase, thereby decreasing extracellular pH and increasing extracellular pCO2. Both decreased pH and increased pCO2 are patent vasodilators of cerebral arterioles.
Surg Neurol 337 2002;57:333–339
Hemodynamically significant stenoses and occlusions of the carotid arteries may result in a pressure drop ipsilateral to the lesion. Several important mechanisms are known to compensate for the hemodynamic compromise caused by extracranial arterial stenosis or occlusion. These pathways are organized in a stepwise fashion: to the first step belong the collaterals of the circle of Willis (anterior and posterior communicating arteries), to the second step the ophthalmic collaterals, and to the third step the leptomeningeal arteries. Finally, if all those collateral compensation capacities become insufficient, the brain tissue is capable of increasing the oxygen extraction from the circulating blood [20,21]. An additional pathomechanism includes vasodilation of the cerebral arterioles: after a certain limit of the pressure drop in the brain tissue is reached, an autoregulatory vasodilation of the cerebral arterioles occurs to ensure better tissue perfusion by decreasing vascular resistance. The theoretical background of the ACZ test in stenoticocclusive lesions is that the pressure drop distal to the lesion induces autoregulatory vasodilation of arterioles. If an autoregulatory vasodilation is present, less or no further vasodilation of the arterioles is possible. Based on the magnitude of the reaction after administering the stimulus, vasodilatory responses can be categorized into the following groups: 1) reduced augmentation of the blood flow relative to the non-stenostic side, 2) absent augmentation of blood flow, 3) paradoxical reduction of the blood flow compared to the resting value [32]. It is widely accepted that cerebral vasoreactivity reflects the hemodynamic status of the cerebral circulation and that impaired hemodynamics are associated with a higher incidence of TIA or stroke [32]. Symptomatic carotid artery occlusions bring about embolic (from the carotid stump, through the external carotid artery, by transhemispheric passage) and hemodynamic strokes [22]. The yearly incidence of stroke has been found to be between 0 to 20% [21,23–25]. It is also clear that impaired or exhausted cerebrovascular reactivity is related to border zone infarcts and indicates poorer prognosis: the combined stroke incidence is 12.5% if cerebrovascular reactivity response is impaired and 41.4% if exhausted. Based on the investigations of the NASCET study [26], the cumulative risk of ipsilateral strokes was 26% in symptomatic carotid artery occlusion. There are data indicating that impaired cerebrovascular reactivity measurements of symptomatic patients have a predictive value in identifying patients who need intraoperative shunt insertion and for whom postoperative improve-
338 Surg Neurol 2002;57:333–339
ment of the intracerebral hemodynamics can be expected [10,27,28]. The significance of cerebral vasoreactivity measurements among asymptomatic patients is still a debated issue. Nighoghossian and co-workers [19] did not find any difference between the CVR of asymptomatic and that of symptomatic patients, while others [29] found that in patients with asymptomatic stenoses or occlusions, there is a side asymmetry of the CVR. There are authors who found that impaired vasoreactivity correlates with a 100% improvement rate of the hemodynamic status after cerebral revascularisation [30], and impaired CVR is accompanied by a higher incidence of stroke [17]. In contrast Fu ¨ rst and co-workers pointed out that in the majority of the asymptomatic patients CVR remains normal [29]. Furthermore, in their study Yonas and co-workers found that an impaired CVR has a predictive value in symptomatic but not in asymptomatic patients [25]. Comparing these observations with our data, it is obvious that administering the vasodilatory stimulus induced statistically significant changes only in the symptomatic carotid artery occlusions and stenoses in our sample. The same was true for cerebrovascular reactivity (actual percent increase of MCAV at different time points after ACZ). Thus, the major finding of our results is that in patients who had symptomatic effects from carotid stenosis or occlusion, a component of their problem is because of compromised collateral capacity of the circle of Willis, as suggested by the compromised reserve capacity. A similar observation was made by Derdeyn with PET OEF measurements showing that the patients who had raised OEF were also the ones who were more likely to be symptomatic [31,32]. In asymptomatic patients the maximal percent increase of the MCAV (CRC) remained comparable on the two sides after injecting the vasodilatory drug. When calculating the side asymmetry of the CRC, only asymptomatic stenosis patients showed a near normal asymmetry index. Although the differences, depicted in Figure 1, are statistically significant and indicate that a hemodynamic compromise in the ipsilateral hemisphere can be expected in symptomatic stenoses, occlusions, and also in asymptomatic occlusions, it has to be noted that standard deviations are relatively high in all groups. This results in a large individual variability of the data despite a statistically demonstrable difference. Further analysis of the data supports this observation, as steal phenomenon was detected in one and impaired reactivity in two patients in the asymptomatic occlusion group, while in patients suffering from symptomatic occlusions two steal phenomena
Orosz et al
and six impaired reserve capacity cases were observed. For stenoses, in the asymptomatic groups one impaired, and in the symptomatic six impaired reserve capacities were found. Thus, in individual cases, a hemodynamic compromise of the cerebral circulation may develop, which results in insufficient collateral capacity, and therefore, may necessitate a cerebral revascularisation procedure. Further prospective, randomized studies using hemodynamic criteria for patient selection are needed to clarify whether the clinical efficiency of carotid endarterectomy and extra-intracranial bypass could be improved. Depending on the results of those studies hemodynamic compromise may become an additional and supporting indication for a reconstructive operation or surgical revascularisation. REFERENCES 1. The EC-IC Bypass Study Group. Failure of extracranial-intracranial bypass to reduce the risk of ischemic stroke. N Engl J Med 1985;313:1191–200. 2. Ausman JI, Diaz FG. Critique of the extracranialintracranial bypass study. Surg Neurol 1986;26:218 – 21. 3. Sundt TM. Was the international randomized trial of extracranial-intracranial bypass representative of the population at risk? N Eng J Med 1987;316:814 – 6. 4. Vorstrup S, Brun B, Lassen NA. Evaluation of the cerebral vasodilatory capacity by the acetazolamide test before EC-IC bypass surgery in patients with occlusion of the internal carotid artery. Stroke 1986;17: 1291– 8. 5. Vorstrup S, Paulson OB. Extracranial-intracranial bypass revisited. Cerebrovasc Dis 1992;2:261–2. 6. European Carotid Surgery Trialists Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:1379 – 87. 7. North American Symptomatic Carotid Endarterectomy Trial Collaboration. Beneficial effect of carotid endarterectomy in symptomatic patients with highgrade carotid stenosis. N Engl J Med 1991;325:445–53. 8. Gorelick PB. Carotid endarterectomy. Where do we draw the line? Stroke 1999;30:1745–50. 9. Ringelstein EB, Zeumer H, Angelou D. The pathogenesis of stroke from internal carotid artery occlusion. Diagnostic and therapeutical implications. Stroke 1983;14:867–75. 10. Baumgartner RW, Regard M. Role of impaired CO2 reactivity in the diagnosis of cerebral low flow infarcts. J Neurol Neurosurg Psychiatr 1994;57:814 –7. 11. Kim JS, Moon DH, Kim GE, et al. Acetazolamide stress brain-perfusion SPECT predicts the need for carotid shunting during carotid endarterectomy. J Nucl Med 2000;41:1836 – 41. 12. Chimowitz MI, Furlan AJ, Jones SC, et al. Transcranial Doppler assessment of cerebral perfusion reserve in patients with carotid occlusive disease and no evidence of cerebral infarction. Neurology 1993;43: 353–7. 13. Cikrit DF, Dalsing MC, Lalka SG, Burt RW, Sawchuk AP,
Cerebrocascular Reactivity in Carotid Stenosis and Occlusion
14. 15.
16. 17. 18.
19.
20.
21.
22. 23.
24. 25.
26.
27. 28. 29.
Solooki BA. The value of acetazolamide single photon emission computed tomography scans in the preoperative evaluation of asymptomatic critical carotid stenosis. J Vasc Surg 1999;30:599 – 605. Dahl A, Russel D, Nyberg-Hansen R, Rootwelt K, Bakke SJ. Cerebral vasoreactivity in unilateral carotid artery disease. Stroke 1994;25:621– 6. Detre JA, Samuels OB, Alsop DC, Gonzalez-at JB, KAsner SE, Raps EC. Noninvasive magnetic resonance imaging evaluation of cerebral blood flow with acetazolamide challenge in patients with cerebrovascular stenosis. J Magn Reson Imaging 1999;10:870 –5. Fu ¨ lesdi B, Limburg M, Bereczki D, et al. Impairment of cerebrovascular reactivity in long-term type 1 diabetes. Diabetes 1997;46:1840 –5. Gur AY, Bova I, Bornstein NM. Is impaired cerebral vasomotor reactivity a predictive factor of stroke in asymptomatic patients? Stroke 1996;27:2188 –90. Hartl WH, Janssen I, Fu ¨ rst H. Effect of carotid endarterectomy on patterns of cerebrovascular reactivity in patients with unilateral carotid artery stenosis. Stroke 1994;25:1952–1957. Nighoghossian N, Trouillas P, Philippon B, Itti R, Adeleine P. Cerebral blood flow reserve assessment in symptomatic versus asymptomatic high-grade internal carotid artery stenosis. Stroke 1994;25:1010 –3. Derdeyn CP, Grubb RL Jr, Powers WJ. Cerebral hemodynamic impairment. Methods of measurement and association with stroke risk. Neurology 1999;53: 251–9. Powers WJ, Press GA, Grubb RL, Gado M, Raichle ME. The effect of hemodynamically significant carotid artery disease on the hemodynamic status of the cerebral circulation. Ann Int Med 1987;106:27–35. Klijn CJM, Kappelle LJ, Tulleken CAF, van Gijn J. Symptomatic carotid artery occlusion. A reappraisal of hemodynamic factors. Stroke 1997;28:2084 –93. Hasegawa Y, Yamaguchi T, Tsuchiya T, Minematsu K, Nishimura T. Sequential change of hemodynamic reserve in patients with major cerebral artery occlusion or severe stenosis. Neuroradiology 1992;34:15–21. Kleiser B, Widder B. Course of carotid artery occlusions with impaired cerebrovascular reactivity. Stroke 1992;23:171–174. Yonas H, Smith HA, Durham SR, Pentheny SL, Johnson DW. Increased stroke risk predicted by compromised cerebral blood flow reactivity. J Neurosurg 1993;79:483–9. Ferguson GG, Eliasziw M, Barr HWK, et al. The North American symptomatic carotid endarterectomy trial. Surgical results in 1415 patients. Stroke 1999;30: 1751– 8. Weiler C, Ringelstein EB, Reiche W, Buell U. Clinical and hemodynamic impacts of low-flow infarcts. Stroke 1991;22:1117–23. Proviciali L, Ceravolo MG, Minciotti P. A transcranial Doppler study of vasomotor reactivity in asymptomatic occlusion. Cerebrovasc Dis 1993;3:27–32. Fu ¨ rst H, Hartl WH, Janssen I. Patterns of cerebrovascular reactivity in patients with unilateral asymptomatic carotid artery stenosis. Stroke 1994;25:1193–200.
Surg Neurol 339 2002;57:333–339
30. Hosoda K, Fujita S, Kawaguchi T, Shose Y, Shibata Y, Tamaki N. Influence of degree of carotid artery stenosis and collateral pathways and effect of carotid endarterectomy on cerebral vasoreactivity. Neurosurgery 1998;42:988 –94. 31. Derdeyn CP, Videen TO, Simmons NR, et al. Countbased PET method for predicting ischemic stroke in patients with symptomatic carotid arterial occlusion. Radiology 1999;212:499 –506. 32. Derdeyn CP, Khosla A, Videen TO, et al. Severe hemodynamic impairment and border zone-region infarction. Radiology 2001;220:195–201.
COMMENTARY
The article by Orosz et al provides one more contribution to our understanding that the world is not all black or white. The argument over whether neurological symptoms are because of emboli and/or hemodynamic events has continued for decades. This article provides another bit of evidence that many, if not most, patients with symptomatic carotid occlusion have symptoms due, if not solely then at least partly, to a chronic compromise of hemodynamics. In an environment of reduced dynamics of the blood stream, it is easy to imagine that a small platelet aggregate could cause a major obstruction while the same platelet aggregate would be rapidly fragmented by normal, highly dynamic pulsatile flow. The authors describe a very simple strategy that can be used in every transcranial Doppler laboratory to understand more about cerebral hemodynamics. The only problem with this strategy is that velocity changes in the middle cerebral artery are not equivalent to flow changes in the cerebral circulation within the parenchyma of the brain. A recent publication suggested that relying only on the transcranial Doppler response to acetazolamide can mislabel as “normal” a group of patients who have the most severe compromise of hemodynamics [1]. Howard Yonas, M.D. Department of Neurological Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania REFERENCES 1. Pindzola RR, Balzer JR, Nemoto EM, Goldstein S, Yonas H. Cerebrovascular reserve in patients with carotid occlusive disease assessed by stable xenon-enhanced CT cerebral blood flow and transcranial Doppler. Stroke 2001;32:1811–7.
Orosz L, Fu ¨ lesdi B, Hoksbergen A, Settakis G, Kolla´r J, Limburg M, Cse´csei G. Assessment of cerebrovascular reserve capacity in asymptomatic and symptomatic hemodynamically significant carotid stenoses and occlusions. Surg Neurol 2002;57:333–339. BACKGROUND
Cerebrovascular reactivity measurements are believed to be a helpful tool for selecting patients who are at higher risk for hemodynamic strokes. The aim of this study was to compare cerebral vasoreactivity among patients suffering from internal carotid artery stenosis of different severity (asymptomatic stenosis, asymptomatic occlusion, symptomatic stenosis, symptomatic occlusion). METHODS
Sixty-two patients with asymptomatic and symptomatic internal carotid artery stenoses and occlusions underwent transcranial Doppler-acetazolamide tests. Absolute velocities of the middle cerebral arteries (MCAV), percent increases of the MCAV at different time points of the test (cerebrovascular reactivity, CVR) and maximal percent increase after administration of acetazolamide (cerebrovascular reserve, CRC) were compared on the affected and non-affected sides. Asymmetry indices (CRC affected side/CRC non-affected side) were compared between the groups of different severity of obstructive lesion. RESULTS
Resting MCAV was similar on both sides in all groups. A significant side-difference of the MCAV values after acetazolamide was observed only in the symptomatic groups. Difference of cerebrovascular reserve capacity between the affected and non-affected side was statistically signif-
Address reprint requests to: Dr Be´la Fu ¨ lesdi, Department of Anesthesiology and Intensive Care, University of Debrecen, Health and Science Center H-4012 Debrecen, Hungary. Received February 14, 2001; accepted November 28, 2001. © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
icant only in the symptomatic groups (CRC symptomatic stenosis 36.6 ⫾ 20.9% vs. 71.1 ⫾ 27.9%, CRC symptomatic occlusion: 31.2 ⫾ 24.6% vs. 64.5 ⫾ 29.7%). Asymmetry index of the CRC was near to 1 in the asymptomatic stenosis group only, while in all the other groups this index referred to a significant hemispheric asymmetry of the vasoreactivity. CONCLUSIONS
Although in general cerebrovascular reserve capacity is compromised in cases of hemodynamically significant carotid lesions, there is a large individual variability within the subgroups. Further randomized studies are needed to clarify whether the clinical efficiency of carotid endarterectomy and extra-intracranial bypass may be improved by selecting the patients using hemodynamic criteria. © 2002 by Elsevier Science Inc. KEY WORDS
Carotid artery stenosis, transcranial Doppler, cerebrovascular reactivity and reserve capacity, acetazolamide.
he role of carotid stenosis in ischemic cerebrovascular diseases has already been known for more than 100 years. Since the first endarterectomy performed by Carrera in 1951, carotid surgery procedures have taken flight. At first the efficacy of extra-intracranial bypass was tested to clarify whether it is superior for preventing ipsilateral strokes compared to conservative therapy. Although the EC-IC Bypass Study Group [1] published a negative result, recent data suggest that in a selected group of patients extra-intracranial bypass may improve the patient’s condition [2–5]. A hemo-
T
0090-3019/02/$–see front matter PII S0090-3019(02)00689-4
334 Surg Neurol 2002;57:333–339
dynamically significant carotid stenosis is proposed to be operated, as was proven by both the ECAS and NASCET trials [6,7]. Although the ACAS trial also showed a beneficial effect of carotid endarterectomy in cases of asymptomatic carotid stenosis, the efficacy of the procedure is still debated, as 83 patients have to be operated on to prevent 1 stroke within 2 years of follow-up [8]. Therefore, recently a more strict patient selection was suggested in cases of asymptomatic carotid stenosis for carotid endarterectomies. The term “more strict patient selection” in the groups of carotid occlusions and asymptomatic stenoses is meant as differentiation of patients who are at higher risk for hemodynamic stroke from those who are at higher risk from embolic stroke. Previous observations suggest that a stroke caused by a hemodynamically significant carotid stenosis or occlusion is in 2/3 of the cases embolic and in 1/3 of the cases hemodynamic in origin [9]. It seems to be logical that a cerebral revascularisation procedure (EC-IC bypass or endarterectomy) has different rates of efficacy in preventing strokes in the two different pathogenetical groups. Besides the assessment of the collateral capacity of cerebral circulation, cerebral vasoreactivity testing has also been used for evaluating patients who have compromised cerebral hemodynamics and, therefore, may be candidates for revascularisation procedures. Carbon dioxide inhalation [10], breath holding test, and acetazolamide have been used for this purpose [11,12]. All these stimuli induce vasodilation of the brain arterioles, resulting in an increase of the cerebral blood flow (CBF). This CBF increase is less if cerebral hemodynamics are compromised and can be diagnosed by different methods, such as SPECT, PET, MR angiography, and transcranial Doppler sonography. In the recent decade, acetazolamide was the most frequently used vasodilatory stimulus for this purpose. So far, the majority of authors have selected groups of patients (asymptomatic or symptomatic stenoses, carotid occlusions), but only a few of them compared cerebral vasoreactivity in patients having different degrees of carotid obstruction. Therefore, in the present study, we wanted to compare cerebrovascular reserve capacity as measured after administration of acetazolamide in patients with symptomatic and asymptomatic carotid stenoses and occlusions. The main goal of the study was to clarify whether there is a difference between the cerebral vasoreactivity in these four different carotid obstructive lesions.
Orosz et al
Patients and Methods Patients were recruited from the Department of Neurology and Neurosurgery at the University of Debrecen Health and Science Center, and from the Department of Vascular Surgery, Academic Medical Center Amsterdam. Asymptomatic carotid stenoses and occlusions were occasionally found through regular ultrasound screening of the carotid arteries before operations for peripheral arterial diseases or open-heart surgery. A patient suffering from carotid artery stenosis or occlusion was considered to be asymptomatic, if there was no amaurosis fugax or neurological symptoms in the previous medical history present and brain computed tomography (CT) scan showed a normal result. Patients with symptomatic stenosis and occlusion were inpatients in the Department of Neurology, University of Debrecen, treated in the Stroke Unit; in these patients either a transient or a permanent neurological deficit could be observed and/or the brain CT showed infarctions. Carotid stenoses and occlusions were diagnosed by the 10 MHz probe of the Hewlett-Packard Sonos 2000 (USA) equipment. Both longitudinal and transverse images were performed. For measuring the severity of the stenosis on the B-mode image, the NASCET criteria were used [7]. After assessing the carotid arteries, transcranial Doppler measurement of the middle cerebral artery was performed on both sides using EME TC 64 B transcranial Doppler sonograph. The vessel was insonated at 50 mm depth. Resting cerebral blood flow velocity measurements were followed by an i.v. administration of 1g of acetazolamide (Diamox, Lederle Parenterals, Puerto Rico). Blood flow velocity measurements were repeated at 10 and 15 minutes after administration of this vasodilatory stimulus. Systolic, diastolic, and mean blood flow velocities, as well as pulsatility indices were registered in every case. For statistical evaluation only mean blood flow velocities were taken into account. Cerebrovascular reactivity was calculated as the percent increase of the mean blood flow velocity after administration of the vasodilatory stimulus according to the following formula:
CVRC ⫽ 100 ⫻ 共MCAVAZ ⫺ MCAVREST) /MCAVREST where MCAVAZ indicates middle cerebral artery mean blood flow velocity after administration of acetazolamide and MCAVREST indicates the resting value of the middle cerebral artery mean blood flow velocity. Similarly, cerebrovascular reserve capacity (CRC) was defined as the maximal percent increase of the blood flow velocity after administra-
Cerebrocascular Reactivity in Carotid Stenosis and Occlusion
1
Surg Neurol 335 2002;57:333–339
Comparison of Middle Cerebral Artery Mean Blood Flow Velocity Values (in cm/s) at Rest and After Injecting Acetazolamide. Means and Standard Deviations
TIME
AFTER ACETAZOLAMIDE (MIN)
0 10 15 0 10 15 0 10 15 0 10 15
AFFECTED (STENOTIC-OCCLUSIVE)
NON-AFFECTED
SIDE
SIDE
P-VALUE
57.6 ⫾ 11.4 86.1 ⫾ 23.0 91.0 ⫾ 23.0
0.84 0.56 0.27
54.6 ⫾ 9.8 79.4 ⫾ 19.2 82.3 ⫾ 19.6
0.18 0.67 0.65
50.1 ⫾ 11.2 78.6 ⫾ 20.4 81.6 ⫾ 18.8
0.11 0.005 0.002
54.2 ⫾ 16.1 84.2 ⫾ 23.5 86.0 ⫾ 24.6
0.79 0.07 0.04
ASYMPTOMATIC OCCLUSION 58.6 ⫾ 16.1 81.3 ⫾ 23.7 81.1 ⫾ 26.6 ASYMPTOMATIC STENOSIS 48.1 ⫾ 16.6 76.4 ⫾ 20.8 79.1 ⫾ 20.9 SYMPTOMATIC STENOSIS (N ⫽ 15) 43.3 ⫾ 11.3 57.0 ⫾ 19.0 57.1 ⫾ 18.5 SYMPTOMATIC OCCLUSION (N ⫽ 15) 55.2 ⫾ 16.2 68.4 ⫾ 23.3 67.4 ⫾ 22.5
tering the vasodilatory stimulus and was calculated as follows:
CRC ⫽ 100 ⫻ 共MCAVAZMAZ ⫺ MCAVREST)/MCAVREST where MCAVAZMAX indicates the maximal increase of the mean blood flow velocity after acetazolamide. The asymmetry index of the cerebrovascular reserve capacity was calculated by dividing CRC on the affected side by CRC on the non-affected side. Statistical evaluation: Means and standard deviations are reported for all values. Parameters with normal distribution were compared with the appropriate t tests. In case of multiple comparisons, Bonferroni corrections were performed. For nonparametric analysis X2 test was used. A p value of ⬍0.05 was accepted as statistically significant. Statistica99 version 5.5 for Windows (StatSoft, Tulsa, Oklahoma) was used for data analysis.
Results Sixty-two patients (42 males and 20 females, mean age: 63.2 ⫾ 9.6 years, ranges: 42– 81 years) suffering from hemodynamically significant stenosis or occlusion of the internal cerebral artery were entered in the study. There were 16 asymptomatic occlusions, 15 symptomatic occlusions, 16 asymptomatic stenoses, and 15 symptomatic stenoses. The distribution of the symptomatic patients according to their stroke subtypes was as follows: in the occlusion group there were 4 TIAs, 1 RIND, 1 minor stroke, 4 progressing, and 4 completed strokes, while in the stenotic group these numbers were
4-2-7-1-0, respectively. The frequency of TIAs, RIND, and progressing strokes did not differ between the two groups, while in the symptomatic occlusion group minor strokes were less frequent (p ⫽ 0.0132, 2 test) and more completed strokes were observed (p ⫽ 0.031, 2 test). Cerebral blood flow velocities in the middle cerebral arteries: Table 1 summarizes mean blood flow velocities of the MCA (MCAV) at rest and after administering acetazolamide. It is obvious from the data that resting cerebral blood flow velocities as measured in the affected and non-affected side were similar in all groups; no side asymmetry was observed. MCAVs did not differ between the two sides after administration of acetazolamide in the asymptomatic groups. In case of symptomatic stenosis, a marked side difference of the MCAV could be observed after administration of acetazolamide, while in symptomatic occlusions this difference was pronounced only 15 minutes after administering the vasodilatory stimulus. Cerebrovascular reactivity and reserve capacity measurements: Calculated cerebrovascular reactivity and reserve capacity values are summarized in Table 2. The percent increase of the MCAV in the asymptomatic groups was similar on both sides at any time after injecting acetazolamide. The same was true for the maximal percent increase of the blood flow velocities (cerebrovascular reserve capacity, CRC). In symptomatic patients, a decreased vasodilatory ability of the cerebral arterioles was detected ipsilateral to the stenotic-occlusive lesion, which was confirmed by lower cerebrovascular re-
336 Surg Neurol 2002;57:333–339
2
Orosz et al
Comparison of Cerebrovascular Reactivity and Reserve Capacity Values in the Different Groups. Values are Shown as Means and Standard Deviations
TIME
AFTER ACETAZOLAMIDE (MIN)
10 15 CRC 10 15 CRC 10 15 CRC 10 15 CRC
AFFECTED (STENOTIC-OCCLUSIVE)
NON-AFFECTED
SIDE
SIDE
ASYMPTOMATIC OCCLUSION 47.1 ⫾ 40.3 48.3 ⫾ 28.4 40.2 ⫾ 30.2 60.0 ⫾ 39.0 45.5 ⫾ 37.4 64.3 ⫾ 34.8 ASYMPTOMATIC STENOSIS 63.6 ⫾ 41.8 45.9 ⫾ 16.7 69.2 ⫾ 39.6 35.9 ⫾ 25.2 70.8 ⫾ 40.3 60.0 ⫾ 20.2 SYMPTOMATIC STENOSIS (N ⫽ 15) 30.9 ⫾ 20.7 59.9 ⫾ 26.7 31.2 ⫾ 20.2 65.7 ⫾ 30.5 36.6 ⫾ 20.9 71.1 ⫾ 27.9 SYMPTOMATIC OCCLUSION (N ⫽ 15) 30.2 ⫾ 24.6 56.4 ⫾ 26.3 31.7 ⫾ 23.5 59.7 ⫾ 28.7 31.2 ⫾ 24.6 64.5 ⫾ 29.7
activity and reserve capacity values on the affected side. Asymmetry index of cerebrovascular reserve capacity: As mentioned in the methods section, the asymmetry index was calculated by dividing CRC of the affected side by that of the non-affected side. Thus, an asymmetry index less than 1 indicates a lower maximal vasodilatory capacity of the middle cerebral artery territory ipsilateral to the stenoticocclusive lesion, whereas an asymmetry index of
1
P-VALUE
0.92 0.157 0.15 0.12 0.26 0.34 0.002 0.001 0.0006 0.004 0.002 0.003
higher than 1 refers to a more pronounced percent increase of the MCAV contralaterally. The calculated asymmetry indices of the cerebrovascular reserve capacities are shown in Figure 1. Although there is a tendency for all stenotic-occlusive lesions but asymptomatic stenosis to have near 0.5 values, indicating lesser maximal vasodilatory capacity ipsilateral to the lesion, very obviously, these indices show high standard deviation values. Thus, there should be a wide variation of patients ranging from
Asymmetry index of the cerebrovascular reserve capacity calculated by dividing values of the stenotic-occlusive by that of the non-stenotic side. “SY” indicates symptomatic, “ASY” indicates asymptomatic.
Cerebrocascular Reactivity in Carotid Stenosis and Occlusion
a low asymmetry index to greater than one. This observation is also supported by the minimal and maximal values of this index (asymptomatic stenosis: 0.4 –2.92, symptomatic stenosis 0.21–1.29, asymptomatic occlusion ⫺0.97–1.43, symptomatic occlusion ⫺0.17–3.06), indicating that there is a wide individual variation of cerebrovascular reserve capacity. If one takes median values into account, asymptomatic stenosis patients have an index of 1.17, which is near to the expected 1, while all the other patients suffering from stenoses or occlusions have lower medians for asymmetry indices (symptomatic stenosis 0.43, symptomatic occlusions 0.51 and asymptomatic occlusions 0.67), indicating that there is a lower cerebral vasoreactivity ipsilateral to the stenotic-occlusive lesion than on the non-affected side.
Discussion We investigated cerebral blood flow velocities and cerebrovascular reserve capacity values in patients suffering from asymptomatic and symptomatic internal carotid artery stenosis and occlusion. We found that resting blood flow velocities are comparable in the affected and non-affected hemispheres in all groups, but cerebrovascular reserve capacity is of lower magnitude on the affected side than the non-affected one in all groups but asymptomatic stenosis. Classification of the patients into subgroups of asymptomatic and symptomatic lesions revealed the most important question at the beginning of the study. A very detailed questionnaire of the previous medical history (including dysesthesias, temporary or permanent weakness of the extremities, speech disturbances, visual symptoms) alone was considered to be uncertain. In our opinion, in some cases temporary circulatory disturbances may be mild and short so the patient does not remember them any more. Therefore, beside clinical criteria we also introduced morphological criteria for patient selection and only patients with negative CT scans and negative medical history of stroke were classified to the asymptomatic group. Another methodological point was the use of transcranial Doppler and acetazolamide as a vasodilatory stimulus. Acetazolamide is a widely accepted stimulus for cerebral hemodynamic studies [13–19]. The drug acts by inhibiting the enzyme carbonic anhydrase, thereby decreasing extracellular pH and increasing extracellular pCO2. Both decreased pH and increased pCO2 are patent vasodilators of cerebral arterioles.
Surg Neurol 337 2002;57:333–339
Hemodynamically significant stenoses and occlusions of the carotid arteries may result in a pressure drop ipsilateral to the lesion. Several important mechanisms are known to compensate for the hemodynamic compromise caused by extracranial arterial stenosis or occlusion. These pathways are organized in a stepwise fashion: to the first step belong the collaterals of the circle of Willis (anterior and posterior communicating arteries), to the second step the ophthalmic collaterals, and to the third step the leptomeningeal arteries. Finally, if all those collateral compensation capacities become insufficient, the brain tissue is capable of increasing the oxygen extraction from the circulating blood [20,21]. An additional pathomechanism includes vasodilation of the cerebral arterioles: after a certain limit of the pressure drop in the brain tissue is reached, an autoregulatory vasodilation of the cerebral arterioles occurs to ensure better tissue perfusion by decreasing vascular resistance. The theoretical background of the ACZ test in stenoticocclusive lesions is that the pressure drop distal to the lesion induces autoregulatory vasodilation of arterioles. If an autoregulatory vasodilation is present, less or no further vasodilation of the arterioles is possible. Based on the magnitude of the reaction after administering the stimulus, vasodilatory responses can be categorized into the following groups: 1) reduced augmentation of the blood flow relative to the non-stenostic side, 2) absent augmentation of blood flow, 3) paradoxical reduction of the blood flow compared to the resting value [32]. It is widely accepted that cerebral vasoreactivity reflects the hemodynamic status of the cerebral circulation and that impaired hemodynamics are associated with a higher incidence of TIA or stroke [32]. Symptomatic carotid artery occlusions bring about embolic (from the carotid stump, through the external carotid artery, by transhemispheric passage) and hemodynamic strokes [22]. The yearly incidence of stroke has been found to be between 0 to 20% [21,23–25]. It is also clear that impaired or exhausted cerebrovascular reactivity is related to border zone infarcts and indicates poorer prognosis: the combined stroke incidence is 12.5% if cerebrovascular reactivity response is impaired and 41.4% if exhausted. Based on the investigations of the NASCET study [26], the cumulative risk of ipsilateral strokes was 26% in symptomatic carotid artery occlusion. There are data indicating that impaired cerebrovascular reactivity measurements of symptomatic patients have a predictive value in identifying patients who need intraoperative shunt insertion and for whom postoperative improve-
338 Surg Neurol 2002;57:333–339
ment of the intracerebral hemodynamics can be expected [10,27,28]. The significance of cerebral vasoreactivity measurements among asymptomatic patients is still a debated issue. Nighoghossian and co-workers [19] did not find any difference between the CVR of asymptomatic and that of symptomatic patients, while others [29] found that in patients with asymptomatic stenoses or occlusions, there is a side asymmetry of the CVR. There are authors who found that impaired vasoreactivity correlates with a 100% improvement rate of the hemodynamic status after cerebral revascularisation [30], and impaired CVR is accompanied by a higher incidence of stroke [17]. In contrast Fu ¨ rst and co-workers pointed out that in the majority of the asymptomatic patients CVR remains normal [29]. Furthermore, in their study Yonas and co-workers found that an impaired CVR has a predictive value in symptomatic but not in asymptomatic patients [25]. Comparing these observations with our data, it is obvious that administering the vasodilatory stimulus induced statistically significant changes only in the symptomatic carotid artery occlusions and stenoses in our sample. The same was true for cerebrovascular reactivity (actual percent increase of MCAV at different time points after ACZ). Thus, the major finding of our results is that in patients who had symptomatic effects from carotid stenosis or occlusion, a component of their problem is because of compromised collateral capacity of the circle of Willis, as suggested by the compromised reserve capacity. A similar observation was made by Derdeyn with PET OEF measurements showing that the patients who had raised OEF were also the ones who were more likely to be symptomatic [31,32]. In asymptomatic patients the maximal percent increase of the MCAV (CRC) remained comparable on the two sides after injecting the vasodilatory drug. When calculating the side asymmetry of the CRC, only asymptomatic stenosis patients showed a near normal asymmetry index. Although the differences, depicted in Figure 1, are statistically significant and indicate that a hemodynamic compromise in the ipsilateral hemisphere can be expected in symptomatic stenoses, occlusions, and also in asymptomatic occlusions, it has to be noted that standard deviations are relatively high in all groups. This results in a large individual variability of the data despite a statistically demonstrable difference. Further analysis of the data supports this observation, as steal phenomenon was detected in one and impaired reactivity in two patients in the asymptomatic occlusion group, while in patients suffering from symptomatic occlusions two steal phenomena
Orosz et al
and six impaired reserve capacity cases were observed. For stenoses, in the asymptomatic groups one impaired, and in the symptomatic six impaired reserve capacities were found. Thus, in individual cases, a hemodynamic compromise of the cerebral circulation may develop, which results in insufficient collateral capacity, and therefore, may necessitate a cerebral revascularisation procedure. Further prospective, randomized studies using hemodynamic criteria for patient selection are needed to clarify whether the clinical efficiency of carotid endarterectomy and extra-intracranial bypass could be improved. Depending on the results of those studies hemodynamic compromise may become an additional and supporting indication for a reconstructive operation or surgical revascularisation. REFERENCES 1. The EC-IC Bypass Study Group. Failure of extracranial-intracranial bypass to reduce the risk of ischemic stroke. N Engl J Med 1985;313:1191–200. 2. Ausman JI, Diaz FG. Critique of the extracranialintracranial bypass study. Surg Neurol 1986;26:218 – 21. 3. Sundt TM. Was the international randomized trial of extracranial-intracranial bypass representative of the population at risk? N Eng J Med 1987;316:814 – 6. 4. Vorstrup S, Brun B, Lassen NA. Evaluation of the cerebral vasodilatory capacity by the acetazolamide test before EC-IC bypass surgery in patients with occlusion of the internal carotid artery. Stroke 1986;17: 1291– 8. 5. Vorstrup S, Paulson OB. Extracranial-intracranial bypass revisited. Cerebrovasc Dis 1992;2:261–2. 6. European Carotid Surgery Trialists Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:1379 – 87. 7. North American Symptomatic Carotid Endarterectomy Trial Collaboration. Beneficial effect of carotid endarterectomy in symptomatic patients with highgrade carotid stenosis. N Engl J Med 1991;325:445–53. 8. Gorelick PB. Carotid endarterectomy. Where do we draw the line? Stroke 1999;30:1745–50. 9. Ringelstein EB, Zeumer H, Angelou D. The pathogenesis of stroke from internal carotid artery occlusion. Diagnostic and therapeutical implications. Stroke 1983;14:867–75. 10. Baumgartner RW, Regard M. Role of impaired CO2 reactivity in the diagnosis of cerebral low flow infarcts. J Neurol Neurosurg Psychiatr 1994;57:814 –7. 11. Kim JS, Moon DH, Kim GE, et al. Acetazolamide stress brain-perfusion SPECT predicts the need for carotid shunting during carotid endarterectomy. J Nucl Med 2000;41:1836 – 41. 12. Chimowitz MI, Furlan AJ, Jones SC, et al. Transcranial Doppler assessment of cerebral perfusion reserve in patients with carotid occlusive disease and no evidence of cerebral infarction. Neurology 1993;43: 353–7. 13. Cikrit DF, Dalsing MC, Lalka SG, Burt RW, Sawchuk AP,
Cerebrocascular Reactivity in Carotid Stenosis and Occlusion
14. 15.
16. 17. 18.
19.
20.
21.
22. 23.
24. 25.
26.
27. 28. 29.
Solooki BA. The value of acetazolamide single photon emission computed tomography scans in the preoperative evaluation of asymptomatic critical carotid stenosis. J Vasc Surg 1999;30:599 – 605. Dahl A, Russel D, Nyberg-Hansen R, Rootwelt K, Bakke SJ. Cerebral vasoreactivity in unilateral carotid artery disease. Stroke 1994;25:621– 6. Detre JA, Samuels OB, Alsop DC, Gonzalez-at JB, KAsner SE, Raps EC. Noninvasive magnetic resonance imaging evaluation of cerebral blood flow with acetazolamide challenge in patients with cerebrovascular stenosis. J Magn Reson Imaging 1999;10:870 –5. Fu ¨ lesdi B, Limburg M, Bereczki D, et al. Impairment of cerebrovascular reactivity in long-term type 1 diabetes. Diabetes 1997;46:1840 –5. Gur AY, Bova I, Bornstein NM. Is impaired cerebral vasomotor reactivity a predictive factor of stroke in asymptomatic patients? Stroke 1996;27:2188 –90. Hartl WH, Janssen I, Fu ¨ rst H. Effect of carotid endarterectomy on patterns of cerebrovascular reactivity in patients with unilateral carotid artery stenosis. Stroke 1994;25:1952–1957. Nighoghossian N, Trouillas P, Philippon B, Itti R, Adeleine P. Cerebral blood flow reserve assessment in symptomatic versus asymptomatic high-grade internal carotid artery stenosis. Stroke 1994;25:1010 –3. Derdeyn CP, Grubb RL Jr, Powers WJ. Cerebral hemodynamic impairment. Methods of measurement and association with stroke risk. Neurology 1999;53: 251–9. Powers WJ, Press GA, Grubb RL, Gado M, Raichle ME. The effect of hemodynamically significant carotid artery disease on the hemodynamic status of the cerebral circulation. Ann Int Med 1987;106:27–35. Klijn CJM, Kappelle LJ, Tulleken CAF, van Gijn J. Symptomatic carotid artery occlusion. A reappraisal of hemodynamic factors. Stroke 1997;28:2084 –93. Hasegawa Y, Yamaguchi T, Tsuchiya T, Minematsu K, Nishimura T. Sequential change of hemodynamic reserve in patients with major cerebral artery occlusion or severe stenosis. Neuroradiology 1992;34:15–21. Kleiser B, Widder B. Course of carotid artery occlusions with impaired cerebrovascular reactivity. Stroke 1992;23:171–174. Yonas H, Smith HA, Durham SR, Pentheny SL, Johnson DW. Increased stroke risk predicted by compromised cerebral blood flow reactivity. J Neurosurg 1993;79:483–9. Ferguson GG, Eliasziw M, Barr HWK, et al. The North American symptomatic carotid endarterectomy trial. Surgical results in 1415 patients. Stroke 1999;30: 1751– 8. Weiler C, Ringelstein EB, Reiche W, Buell U. Clinical and hemodynamic impacts of low-flow infarcts. Stroke 1991;22:1117–23. Proviciali L, Ceravolo MG, Minciotti P. A transcranial Doppler study of vasomotor reactivity in asymptomatic occlusion. Cerebrovasc Dis 1993;3:27–32. Fu ¨ rst H, Hartl WH, Janssen I. Patterns of cerebrovascular reactivity in patients with unilateral asymptomatic carotid artery stenosis. Stroke 1994;25:1193–200.
Surg Neurol 339 2002;57:333–339
30. Hosoda K, Fujita S, Kawaguchi T, Shose Y, Shibata Y, Tamaki N. Influence of degree of carotid artery stenosis and collateral pathways and effect of carotid endarterectomy on cerebral vasoreactivity. Neurosurgery 1998;42:988 –94. 31. Derdeyn CP, Videen TO, Simmons NR, et al. Countbased PET method for predicting ischemic stroke in patients with symptomatic carotid arterial occlusion. Radiology 1999;212:499 –506. 32. Derdeyn CP, Khosla A, Videen TO, et al. Severe hemodynamic impairment and border zone-region infarction. Radiology 2001;220:195–201.
COMMENTARY
The article by Orosz et al provides one more contribution to our understanding that the world is not all black or white. The argument over whether neurological symptoms are because of emboli and/or hemodynamic events has continued for decades. This article provides another bit of evidence that many, if not most, patients with symptomatic carotid occlusion have symptoms due, if not solely then at least partly, to a chronic compromise of hemodynamics. In an environment of reduced dynamics of the blood stream, it is easy to imagine that a small platelet aggregate could cause a major obstruction while the same platelet aggregate would be rapidly fragmented by normal, highly dynamic pulsatile flow. The authors describe a very simple strategy that can be used in every transcranial Doppler laboratory to understand more about cerebral hemodynamics. The only problem with this strategy is that velocity changes in the middle cerebral artery are not equivalent to flow changes in the cerebral circulation within the parenchyma of the brain. A recent publication suggested that relying only on the transcranial Doppler response to acetazolamide can mislabel as “normal” a group of patients who have the most severe compromise of hemodynamics [1]. Howard Yonas, M.D. Department of Neurological Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania REFERENCES 1. Pindzola RR, Balzer JR, Nemoto EM, Goldstein S, Yonas H. Cerebrovascular reserve in patients with carotid occlusive disease assessed by stable xenon-enhanced CT cerebral blood flow and transcranial Doppler. Stroke 2001;32:1811–7.