Effect of Acetazolamide Reactivity and Long-term Outcome in Patients With Major Cerebral Artery Occlusive Diseases
To the Editor:
We read the report published in Stroke by Yokota et al1 with great interest. This is a potentially important article because it documented the cerebrovascular reactivity in a group of patients with advanced occlusive vascular disease and then observed the subsequent stroke rate. The existence of a high-risk subgroup of patients due to hemodynamic compromise continues to be debated, as does the potential role of extracranial-intracranial (EC-IC) bypass surgery for the treatment of that subgroup. Unfortunately, in our opinion, the author’s conclusion that cerebrovascular reactivity defined by the cerebral blood flow response to acetazolamide did not identify a subgroup at high risk for stroke is not substantiated by the study design or the data presented.
While the study began with a relatively large population of 105 patients with advanced occlusive vascular disease, 11 were lost to follow-up and 16 went on to surgical interventions. Although an explanation for the carotid endarterectomies is presented, none is given for the 9 EC-IC bypass procedures. This point alone invalidates this study as a prospective natural history study because of the withdraw of a significant number of patients without meeting a prospectively decided end point, ie, stroke or death. Because these patients underwent a purely hemodynamic procedure, the authors must have perceived that these individuals were at increased risk of stroke. These 9 individuals were the ones who were likely to have been of greatest interest to this study.
Despite the authors’ claim that single-photon emission computed tomography (SPECT) with N-isopropyl-p-[123I]-iodoamphetamine ([123I]IMP) is a useful technology for identifying patients with hemodynamic reserve compromise, there is ample literature to make this claim doubtful. The SPECT study used by Yokota et al1 involved 2 studies performed 3 days apart. This long separation of baseline and acetazolamide-activated studies is a less-than-desirable study format, because many variables may have changed significantly between studies. Both the transcranial Doppler and xenon-enhanced CT cerebral blood flow studies that the authors criticize as being flawed were based on challenge studies performed 20 minutes apart.2 3 4
It must be remembered that [123I]IMP SPECT is a qualitative technology which must base its conclusions on patterns and changes of patterns of flow between a symptomatic and an asymptomatic vascular territory. Because this qualitative technology is only able to examine the change of ratios, such a study is unable to distinguish a negative flow response from an asymmetrical positive response. Because only a negative cerebral blood flow response (“steal phenomenon”) was found to be predictive of an increased stroke4 5 as well as an increased oxygen extraction fraction,6 it is very likely that patients with a bilateral drop of flow as well as an asymmetrical activation of flow were misclassified by Yokata et al1 in regard to a vascular reserve compromise. In an analysis of the value of quantitative versus qualitative data in making the above “correct” decision, qualitative data had a 50% error of prediction (sensitivity and specificity).7
Unfortunately, only 32 patients with carotid occlusion were enrolled into the study, with the remainder of the patients having either internal carotid artery or middle cerebral artery stenosis. Because the recognized important role of continued embolic events in patients with internal carotid artery stenosis (and, from the authors’ personal experience, with middle cerebral artery stenosis), this study, despite its claim of being a large, prospective trial based on a reliable methodology, has fallen short in all regards.
The authors’ conclusion that reduced vasodilatory capacity does not play a major role in stroke recurrence would seem premature. The weight of the literature, including a recent study by Powers et al,8 has demonstrated that a hemodynamically compromised subgroup at increased risk for stroke does exist and can be identified by quantitative technologies capable of identifying either a steal phenomenon or an increased oxygen extraction fraction. A future study for examination of this question should ideally examine both the ideal methodology for identifying the subgroup at risk as well as the efficacy of a surgical revascularization procedure randomized for only the group at increased risk of stroke.
- Copyright © 1998 by American Heart Association
Yokota C, Hasegawa Y, Minematsu K, Yamaguchi T. Effect of acetazolamide reactivity and long-term outcome in patients with major cerebral artery occlusive diseases. Stroke.. 1998;29:640–644.
Kleiser B, Widder B. Course of carotid artery occlusion with impaired cerebrovascular reactivity. Stroke.. 1992;23:171–174.
Nariai T, Suzuki R, Hirakawa K, Maehara T, Ishii K, Senda M. Vascular reserve in chronic cerebral ischemia measured by the acetazolamide challenge test: comparison with positron emission tomography. AJNR Am J Neuroradiol.. 1995;16:563–570.
Powers WJ, Derdeyn CP, Yundt KD, Carpenter DA, Videen TO, Fritsch SM, Spitznagel EL, Grubb RL Jr. PET predicts subsequent stroke in symptomatic patients with carotid occlusion. Paper presented at: Annual Meeting of the American Academy of Neurology; April 25–May 2, 1998; Minneapolis, Minn.
In our recent article,R1 we reported that reduced cerebral hemodynamic capacity, determined by SPECT and acetazolamide (ACZ) challenge in patients with cerebral artery occlusive disease, does not play a major role in occurrence of subsequent stroke. The study was performed in a prospective manner. Each subject was evaluated on admission by CT scan, cerebral angiography, and ACZ-SPECT. Patients with infarcts of medium to large size and those with multiple, bilateral carotid, or vertebrovasilar arterial lesions were carefully excluded, because these lesions not only make the judgment of ACZ reactivity difficult but also affect the patients’ outcome. We examined a total 105 patients for up to 7.8 years. We believe this to be the most comprehensive and informative study concerning the effect of vasoreactivity on the outcome currently available in the literature. Drs Yonas and Pindzola raise several important questions regarding our study.
Their first question concerns the 9 patients who underwent the EC-IC bypass procedure. Our protocol did not put any restrictions on the medical management or surgical procedures. Within these guidelines, EC-IC bypass surgery was performed on 9 patients, including 6 ACZ-positive patients who had reduced vasodilatory capacity. Withdrawal of these patients might have appeared to affect our results; however, when they were included in the survival analysis with respect to stroke recurrence at the time of the surgery, no significant differences were observed in the overall recurrence-free survival rate between the ACZ-positive and ACZ-negative groups.
The second point raised by Drs Yonas and Pindzola relates to the SPECT methodology. We used a relative change in CBF distribution between 2 hemispheres to evaluate ACZ reactivity. The absolute CBF value may be affected by many variables, including arterial CO2 tension, arousal level, and measurement conditions. However, the flow pattern tends to remain stable. Because all patients had an angiographically proved unilateral occlusive vascular lesion, vasodilatory capacity in the contralateral hemisphere could be used as an internal control for each patient. All SPECT studies were performed at least 1 month after the ischemic event. During the 3-day interval between baseline and ACZ challenge, the cerebral hemodynamics were assumed to be stable. We demonstrated that our SPECT method with ACZ challenge was reliable on the basis of the close correlation between these results and those obtained with the oxygen extraction fraction and cerebral blood volume/cerebral blood flow ratio simultaneously measured by positron emission tomography (PET) using 15O-labeled gas.R2 Drs Yonas and Pindzola suggest that the steal phenomenon is predictive of a subsequent stroke. A varying degree of vasodilatory capacity may correlate with severity of local hemodynamic failure as demonstrated by PET. However, the clinical accuracy of the predictive ability of the steal phenomenon for stage II hemodynamic failure remains in question. We demonstrated that the paradoxical decrease phenomenon is highly specific to stage II failure (98% specificity) but its sensitivity is very low (45% sensitivity), based on simultaneous measurement of absolute cerebral blood flow change after the ACZ challenge and several other PET parameters using PET with 15O-H2O injection and 15O-gas inhalation.R3
As for the patient characteristics, stenosis of the middle cerebral artery (MCA) causes less than 5% of the ischemic strokes among Western populations.R4 R5 Furthermore, intracranial arterial lesions occur more frequently in Japanese than in Western populations. A report by the National Cardiovascular Center Stroke RegistryR6 that included 2192 stroke patients showed that the frequency of extracranial arterial lesions among atherothrombotic stroke patients was 50% and that of intracranial lesions 40%; the lesion responsible could not be determined in the remaining 10% (authors’ unpublished data, 1998). These values are similar to those of the present study. Thus, the relatively small number of patients with internal carotid artery (ICA) occlusion in our study appears to reflect the ethnic differences in the distribution of atherosclerotic vessels. The ACZ reactivity became normal within an average of 2 years in 11 of 24 patients who initially demonstrated reduced ACZ reactivity in our study. Of those 11 patients, 5 had MCA stenosis, 1 had MCA occlusion, 3 had ICA stenosis, and 2 had ICA occlusion. These data indicate that spontaneous improvement in reduced vasodilatory capacity can also be expected in cases of carotid occlusion.
The significance of chronic hemodynamic insufficiency in stroke occurrence has been a matter of controversy. As recently discussed by Barnett,R7 uncontrolled case series reports and retrospective studies may raise hopes but will prove nothing. Only a well-designed prospective, randomized study can solve this important question. However, before starting such a large trial, we should systematically accumulate data on stroke occurrence in patients with major cerebral artery disease, clarify the target population for a future study, and most importantly, standardize the method of evaluating “chronic hemodynamic insufficiency.”
Yokota C, Hasegawa Y, Minematsu K, Yamaguchi T. Effect of acetazolamide reactivity on long-term outcome in patients with major cerebral artery occlusive diseases. Stroke.. 1998;29:640–644.
Hirano T, Minematsu K, Hasegawa Y, Tanaka Y, Hayashida K, Yamaguchi T. Acetazolamide reactivity on 123I-IMP single-photon emission computed tomography in patients with major cerebral artery occlusive disease: correlation with positron emission tomography parameters. J Cereb Blood Flow Metab.. 1994;14:763–770.
Hasegawa Y, Minematsu K, Matsuoka H, Imamura T, Tanaka Y, Hayashida K, Yamaguchi T. CBF responses to acetazolamide and CO2 for the prediction of hemodynamic failure: a PET study. Stroke.. 1997;28:242. Abstract.
Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction: the Northern Manhattan Stroke Study. Stroke.. 1995;26:14–20.
Caplan L, Babikian V, Helgason C, Hier DB, DeWitt D, Patel D, Stein R. Occlusive disease of the middle cerebral artery. Neurology.. 1985;35:975–982.
Yokota C, Minematsu K, Hasegawa Y, Yamaguchi T. Determinants of recurrent stroke and death by stroke subtypes: a NCVC Stroke Registry. Stroke.. 1998;29:321. Abstract.
Barnett HJM. Hemodynamic cerebral ischemia: an appeal for systematic data gathering prior to a new EC/IC trial. Stroke.. 1997;28:1857–1860.\.