Department of Neurological Surgery,
University of Pittsburgh,
Pittsburgh, Pennsylvania
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.
References
1.
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.
2.
Kleiser B, Widder B. Course of carotid artery
occlusion with impaired cerebrovascular reactivity. Stroke.. 1992;23:171–174.
3.
Kuroda S, Kamiyama H, Abe H, Houkin K, Isobe M,
Mitsumori K. Acetazolamide test in detecting reduced
cerebral perfusion reserve and predicting long-term prognosis in
patients with internal carotid artery occlusion.
Neurosurgery.. 1993;32:912–919.[Medline]
[Order article via Infotrieve]
4.
Yonas H, Smith HA, Durham SR, Pentheny SL, Johnson DW.
Increased stroke risk predicted by compromised cerebral blood flow
reactivity. J Neurosurg.. 1993;79:483–489.[Medline]
[Order article via Infotrieve]
5.
Webster MW, Makaroun MS, Steed DL, Smith HA, Johnson
DW, Yonas H. Compromised cerebral blood flow reactivity is a predictor
of stroke in patients with symptomatic carotid artery
occlusive disease. J Vasc Surg.. 1995;21:338–345.[Medline]
[Order article via Infotrieve]
6.
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.[Abstract]
7.
Yonas H, Pindzola RR, Meltzer CC, Sasser H.
Qualitative versus quantitative assessment of cerebrovascular reserves.
Neurosurgery.. 1998;42:1005–1012.[Medline]
[Order article via Infotrieve]
8.
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.
Cerebrovascular Division,
Department of Medicine,
National Cardiovascular Center,
Osaka, Japan
In our recent article,1 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.2 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.3
As for the patient characteristics, stenosis of the middle
cerebral artery (MCA) causes less than 5% of the ischemic
strokes among Western populations.4 5 Furthermore,
intracranial arterial lesions occur more frequently in
Japanese than in Western populations. A report by the National
Cardiovascular Center Stroke Registry6
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,7 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."
References
1.
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.
2.
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.[Medline]
[Order article via Infotrieve]
3.
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.
4.
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.
5.
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.
6.
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.
7.
Barnett HJM. Hemodynamic cerebral
ischemia: an appeal for systematic data gathering prior to a
new EC/IC trial. Stroke.. 1997;28:1857–1860.\.
© 1998 American Heart Association, Inc.
Letters to the Editor
Effect of Acetazolamide Reactivity and Long-term Outcome in Patients With Major Cerebral Artery Occlusive Diseases
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