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(Stroke. 1996;27:425-430.)
© 1996 American Heart Association, Inc.

Articles

Persisting Perfusion Defect in Transient Ischemic Attacks

A New Clinically Useful Subgroup?

Patrice Laloux, MD; Jacques Jamart, MD; Hubert Meurisse, BSc; Patrick De Coster, MD Christian Laterre, MD, PhD

From the Departments of Neurology (P.L., C.L.), Nuclear Medicine (H.M., P. De C.), and Biostatistics (J.J.), Mont-Godinne University Hospital, Louvain University Medical School, Yvoir, Belgium.

Correspondence to Patrice Laloux, MD, Department of Neurology, Mont-Godinne University Hospital, B-5530 Yvoir, Belgium.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Cerebral infarction and prolonged regional hypoperfusion have been described in patients with transient ischemic attacks (TIAs). The aim of this study was to compare the sensitivity of single-photon emission CT (SPECT) with that of brain CT and to evaluate the clinical significance of differentiation of TIA patients with or without focal hypoperfusion.

Methods From a hospital-based population, we studied the SPECT and CT findings in 76 consecutive patients, without a stroke history, who presented with TIA in the carotid artery territory. The recorded variables were the time of SPECT imaging (<36 or 36 hours), clinical presentation, history of previous TIA(s), duration of the presenting attack (<2 or 2 hours), vascular risk factors, and etiology. We used both visual and semiquantitative analyses for the SPECT evaluation. Acetazolamide challenge was not performed.

Results The overall SPECT sensitivity was 36% (27/76). When brain CT and SPECT were performed in the same patients, the SPECT sensitivity was significantly higher than that of CT (19/59 [32%] versus 8/59 [14%]; P=.007). The SPECT sensitivity was not dependent on the time of investigation, duration of attacks, history of TIA(s), or the clinical presentation. The vascular risk and etiologic factors were not significantly different between the patients with or without prolonged focal hypoperfusion. Logistic regression did not identify any variable to discriminate the two groups.

Conclusions Despite its better sensitivity compared with CT, SPECT performed without the acetazolamide test provides no additional clinically useful information on the vascular risk factors and etiology in TIA patients.

Key Words: cerebral ischemia, transient • diagnostic imaging • tomography, emission-computed

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
By definition, TIAs do not leave a neurological deficit beyond 24 hours after onset.¹ However, a subgroup of TIA patients with infarction on brain CT has been defined and termed CITS.^{2 3 4 5 6 7 8 9 10} The prevalence of an appropriate ischemic lesion was 2% to 31%^{9 11 12 13 14 15 16 17 18 19} on CT and 77% on MRI.⁹ It has been suggested that these patients were different in etiological factors, duration, and prognosis.^{13 15 17 20 21 22 23 24} This subgroup was also regarded as a continuum between TIA without infarction and ischemic stroke.^{16 19 24 25} In the same way, several studies have reported regional hypoperfusion in some TIA patients.^{12 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43} The aim of our study was to assess SPECT and CT sensitivity in a large group of consecutive patients with TIA in the carotid artery territory. Referring to CITS, we also addressed the issue of whether TIA patients with a relevant persisting focal hypoperfusion should be differentiated from those without hypoperfusion in terms of duration of attacks, history of previous TIAs, clinical presentation, vascular risk factors, and etiology. The results should evaluate the clinical significance of such a differentiation in the therapeutic management of these patients.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Between February 1989 and May 1994, the Mont-Godinne Stroke Data Bank prospectively collected the data of 523 patients admitted to the Department of Neurology for an acute cerebral ischemic event. From this cohort, 147 patients presented with TIA defined according to the National Institute of Neurological Disorders and Stroke classification.¹ All patients were examined by a neurologist, and the diagnosis was carefully and independently reviewed by one of us (P.L.). We excluded 2 patients with a questionable diagnosis of TIA, 3 with isolated amaurosis fugax, and 22 with transient ischemia involving the posterior circulation. SPECT was not performed in 23 outpatients. Thirteen patients with a history of stroke were excluded. The SPECT studies had not been backed up in 8 patients and thus were not available for further computerized analysis. We therefore selected 76 consecutive patients (55 men, 21 women) aged 30 to 84 years (mean, 66±11 years; median, 67 years) who presented with TIA in the carotid artery territory and were studied with ^99mTc-labeled HMPAO SPECT. The vascular territory was determined by the neurological examination on admission. Lacunar syndrome was defined as follows: pure motor syndrome, pure sensory syndrome, pure sensorimotor syndrome, ataxic hemiparesis, and dysarthria-clumsy hand syndrome. Carotid superficial ischemic syndrome was defined by the presence of hemiplegia with predominant brachiofacial involvement, monoplegia/hypesthesia, and neuropsychological impairment (aphasia, anosognosia, apraxia, asomatognosia, and unilateral neglect). Patients with superficial ischemic syndrome were further divided into two subgroups with or without neuropsychological impairment. The following investigations were performed: laboratory tests, cervical Doppler ultrasound study, transcranial Doppler, arterial selective angiography of the extracranial and intracranial arteries in selected patients, 12-lead electrocardiogram, 24-hour electrocardiographic Holter monitoring, and transthoracic echocardiography. Twenty-nine patients with apparently cryptogenetic TIA underwent transesophageal echocardiography. The definitions of the vascular risk factors and etiologies of the qualifying event were the same as those used in a previous study.⁴⁴ All patients received standard treatment, including hemodilution when hematocrit level was greater than 45% and acetylsalicylic acid (500 mg/d) or anticoagulant in case of cardiac-source emboli. Six patients underwent ipsilateral carotid endarterectomy.

A CT scan with contrast (Siemens DRH) was obtained in 59 patients (78%) at least 48 hours after onset with a mean time interval of 5 days (range, 2 to 9 days). In the remaining 17 patients, a second control CT could not be obtained because of the lack of availability of our single CT scan in the early phase of our study. Contiguous axial slices (matrix of 512 pixels) were obtained parallel to the canthomeatal line. Slice thickness was 4 mm (scan time, 7 seconds per slice) in the posterior fossa and 8 mm (scan time, 5 seconds per slice) in the cerebral hemispheres. Acute or subacute cerebral infarct was defined by the presence of at least one of the following CT characteristics: focal hypodensity, mass effect on adjacent ventricles and cerebral sulci and fissures, and peripheral contrast enhancement.⁴⁵ In the 59 patients with a CT scan performed after 48 hours, topography of infarcts was classified according to the vascular anatomic territory.⁴⁶ The definitions of cortical and subcortical infarct have been described in detail elsewhere.⁴⁷ Special attention was paid to differentiate silent infarcts from acute or subacute infarcts. The CT criteria of chronic cerebral infarct have been reported elsewhere.⁴⁴

rCBF was measured with brain SPECT after the intravenous injection of 20 mCi (740 MBq) ^99mTc-HMPAO (Ceretec, Amersham) with the patient under resting conditions with eyes open in a dim, quiet room. Acquisition was performed 10 to 30 minutes after injection of the tracer with a single-head rotating gamma camera (General Electric; 64 projections of 30 seconds each; spatial resolution of 12 mm, full width at half maximum). Filtered backprojection with linearization was performed for data reconstruction with the use of a Sheeplogan filter (with Hanning window), which is a modified version of the Ramp filter. Correction of scatter and attenuation were removed to improve the processing time. A correction factor to limit hyperfixation error in patients evaluated in the subacute phase⁴⁸ had not yet been implemented routinely at the time of this study. The raw data were first compressed to permit reconstruction of consecutive parallel axial slices every 12 mm parallel to and above the orbitomeatal line. SPECT findings were blindly evaluated by the Department of Nuclear Medicine without knowledge of the clinical data. Visual and semiquantitative analyses were performed. For visual analysis, axial, coronal, and sagittal maps were studied. For quantification, with a computerized program developed in our laboratory, 16 symmetrical ROIs (ROIs of 3x3 pixels; pixel size, 6 mm) were automatically located, 6 along the cortical ribbon over each cerebral hemisphere and 2 over each cerebellar hemisphere. Given the poor spatial resolution of our single-head camera, ROIs were not placed in subcortical regions. The images in the inferior anterior temporal and high vertex cortical regions were excluded because of greater side-to-side variability. In each ROI, the difference in total count was expressed as a percentage of the value from the contralateral asymptomatic hemisphere with a normal cerebral blood flow. We studied 9 control patients (3 men, 6 women) aged 30 to 62 years (mean, 40±10 years) suffering from tension-type headache, in whom a CT scan was normal (P.L. et al, unpublished data, 1994). The mean of interhemispheric differences was 1.01±0.04 and 1.00±0.04 for the right and left cerebral ROIs, respectively. An interhemispheric difference of at least 10% was therefore considered to be significant, as in two other studies using the same methodology.^{36 49} For each patient, significant hypoperfusion was recorded when the visual and semiquantitative analyses were in agreement. The degree of hypoperfusion was defined by the highest degree of hypoperfusion. SPECT examinations took place within the first 36 hours in 51 patients (67%), with a mean time interval of 18 hours and 41 minutes (range, 4 hours and 2 minutes to 32 hours and 22 minutes; median, 21 hours and 30 minutes). In the remaining 25 patients, the mean time interval was 4 days (median, 3 days). The acetazolamide test was not performed.

SPECT and CT sensitivity were calculated as the percentage of patients who had focal hypoperfusion or hypodensity related to the qualifying event, respectively. Hyperperfusion was not taken into account for the assessment of SPECT sensitivity. SPECT sensitivity was also studied depending on whether the examination was performed within 36 hours or more than 36 hours after the onset. Furthermore, we tried to determine whether the duration of TIAs, history of TIAs in the same vascular territory, clinical presentation, and vascular risk and etiological factors were different in patients with or without a persisting perfusion defect.

Numerical variables were expressed as mean±SD. Sensitivities of SPECT or CT were compared between two groups of patients by ² or Fisher's exact tests. The binomial test was used to compare the SPECT and CT sensitivities in the same patients. Logistic regression was performed to select variables discriminating between the patients with or without hypoperfusion. All statistical tests were two-tailed. Analysis was performed by SC (Lambda-Plus) and SPSS (SPSS Inc) statistical software.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this population of 76 consecutive TIA patients, the clinical examination showed a lacunar syndrome and a carotid superficial ischemic syndrome in 32 (42%) and 44 patients (58%), respectively (Table 1). The mean duration of TIAs was 2 hours and 14 minutes (range, 1 minute to 24 hours; median, 52 minutes). Forty-seven patients (62%) had attacks lasting less than 60 minutes. Previous TIA(s) were reported in 36 patients (47%). They were localized in the same vascular territory as that of the qualifying event in 29 patients (80%) and in another territory in 14 (39%). Seven patients had several attacks in different territories. In 23 patients with prior TIA(s) in the same vascular territory, the mean number of episodes preceding the last ischemic attack within the first week before admission was 1.7 (range, 1 to 7).

View this table: [in this window] [in a new window]   Table 1. SPECT Sensitivity in TIAs

The CT scan showed a relevant infarct in 14% (8/59). The topography was cortical in 2 patients and deep in 6. Silent strokes were noted in 18 patients (30%). All were deep lacunar infarcts (2 cm). SPECT showed a focal hypoperfusion on the contralateral to the lesion in 2 patients (3%) in whom CT demonstrated no silent infarcts. Thus, SPECT showed a relevant regional hypoperfusion in 36% (27/76). Six of the 8 patients with a CT-proven infarct had a relevant hypoperfusion. In the 2 remaining patients, SPECT was normal despite a deep-seated lacunar infarct localized in the posterior limb and the anterior limb of the internal capsule, respectively. In the 2 patients with a cortical infarct, the topography of the hypoperfusion correlated well with the tissue necrosis. In 4 patients, the CT scan showed a lacunar silent infarct ipsilateral to the hypoperfusion. In the patients in whom both examinations were performed, the SPECT sensitivity was significantly higher than that of CT (32% versus 14%; P=.007). The mean degree of hypoperfusion was 14±4% (range, 10% to 23%; median, 13%). When the examination took place within or after 36 hours, the SPECT sensitivity was 36% and 35%, respectively.

The SPECT sensitivity was not significantly different according to the duration of TIAs or the clinical presentation (Table 1). Likewise, a history of TIA(s) in the same vascular territory as that of the qualifying event was not associated with a higher rate of abnormal SPECT (Table 1). Eight of the 12 patients with large-artery disease had a severe carotid occlusive lesion (1 occlusion with contralateral >80% carotid stenosis, 1 occlusion without contralateral stenosis, 6 ipsilateral >75% stenosis). SPECT showed a persisting ipsilateral hypoperfusion in 3 of these patients. The vascular risk factors and etiology were not significantly different between the patients with or without hypoperfusion (Table 2). A logistic regression did not identify any variable to discriminate between the two groups.

View this table: [in this window] [in a new window]   Table 2. Vascular Risk Factors and Etiology in Patients With or Without Hypoperfusion

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Since our study was not strictly prospective, the patients could not be studied with SPECT and CT with the same time interval from the onset. The delay of admissions and the short duration of TIAs (60 minutes in 62% of patients) prevented us from performing SPECT imaging during the attack. This study included all consecutive patients with TIA in the carotid territory whatever the etiology, unlike many other series. However, our population was not strictly unselected because it was hospital-based and the patients with a history of stroke were excluded.

The 14% prevalence of appropriate infarct on CT was in agreement with that found in other series.^{14 16 17 18 19} Similar to the findings of Isaka et al⁴³ we found that the SPECT sensitivity was significantly higher than that of CT. The mild perfusion defect in our TIA patients (mean interhemispheric difference, 14%) contrasts with the higher degree of hypoperfusion (20%) that we previously reported in carotid infarcts.⁴⁷ Similarly, Yonekura et al²⁹ found a lower asymmetry index in TIA patients than in patients with minor strokes. Therefore, a combination of visual and semiquantitative analyses is required to increase the reliability of SPECT. In the published studies, which used different methodologies and variable admission times, the percentages of abnormal SPECT were in a very large range. When the findings of angiograms were not detailed, the sensitivity was 0% to 89%.^{30 31 32 34 36 37 38} In patients with normal carotid angiograms, the sensitivity varied between 8% and 64%.^{26 27 41 42} On the other hand, in selected patients with occlusive carotid disease, several authors^{12 28 35 39 42} reported a higher sensitivity ranging from 47% to 100%, except for Russel et al⁴⁰ and Hemmingsen et al,³³ who found a lower sensitivity of 14% and 27%, respectively. In nonselected patients, the SPECT sensitivity in our study (36%) was lower than that found by Isaka et al (67%).⁴³ This lower sensitivity might be due to deep ischemic lesions undetected by the low spatial resolution of our single-head camera, although it did not appear to be dependent on the vascular territory defined by the clinical presentation. Another explanation might be the long time interval between the onset and the SPECT imaging, but unlike other reports,^{26 31 38} the sensitivity in our study was not significantly different when the examination took place within or after 36 hours. When SPECT examinations were repeated at different times in the same patients, Hartmann³¹ reported sequential changes of rCBF with early or delayed return to normal in some patients. Yet, even if most patients have normal rCBF in the acute or subacute phase, a number of patients may have persisting flow abnormalities as late as 90 days despite the recovery of their clinical deficits.^{26 35} Several authors reported that acetazolamide, a carbonic anhydrase inhibitor,^{50 51} or CO₂,⁵² which both induce dilatation of the cerebral microvasculature, significantly increased the SPECT sensitivity for detecting pathological areas in TIA patients with or without occlusive carotid disease.^{35 39 40 53 54} Vasoreactivity tests, which were not routinely performed in our study, would have probably improved the SPECT sensitivity in our series as well as the use of dedicated or three-head cameras.

We attempted to determine the clinical significance of persisting hypoperfusion in relation to CITS. The patients with attacks lasting more than 120 minutes had regional hypoperfusion more frequently but not significantly so. Kassiotis and Steinling,³⁵ however, found a possible relationship between the duration of attacks and the presence of hypoperfusion in 4 patients with TIAs due to emboli. Our data show that the vascular risk and etiological factors were not different between the patients with or without regional hypoperfusion. Even though hypoperfusion was more often associated with large-artery disease and normal SPECT with small-vessel disease, the difference was not significant. In addition, the logistic regression did not identify any variable to discriminate the two groups. Yet, in other studies,^{12 35 39 53} SPECT showed a focal persisting hypoperfusion in patients with occlusive carotid disease and hemodynamic insufficiency. Chollet et al³⁹ found in 15 TIA patients an association between the degree and size of hypoperfusion and a severe carotid atherosclerotic lesion. In two studies,^{35 39} vasoreactivity challenge with acetazolamide could discriminate the TIAs due to thromboemboli from those secondary to a carotid stenosis that was hemodynamically significant.

In our 2 patients with cortical infarcts, the rCBF decrease correlated well with the tissue necrosis. In the CT-proven deep-seated infarcts, the chronic cortical flow reduction was probably caused by functional inactivation (diaschisis).^{54 55 56 57 58} In addition to the decrease of the functional input to the cortex, the white matter damage can lead to retrograde degeneration and selective cell necrosis in the cortex, which might explain the persistence of remote cortical hypoperfusion.⁵⁹ On the other hand, in the patients without a well-demarcated infarct on CT, the mechanism remains unclear. The role of old silent lacunar infarcts or lacunar infarcts undetected on CT cannot be entirely excluded, but a remote hypoperfusion due to undetectable tiny infarcts is unlikely.⁶⁰ In the patients with carotid occlusive disease, a chronic regional hemodynamic insufficiency might also explain the persisting hypoperfusion. The extension of cerebral infarct depends in part on the collateral circulation, which can improve the transiently impaired perfusion and prevent tissue necrosis.^{61 62 63 64} The collateral supply would be adequate to protect the brain tissue against its transformation into complete infarct but not enough to restore a normal rCBF. However, the neuronal function would be preserved without residual neurological deficit because the rCBF remains above the threshold of electric failure⁶⁵ or because the brain oxygen extraction from the blood is increased⁶⁶ to maintain adequate cerebral metabolism. However, this hemodynamic mechanism does not apply to the patients without carotid occlusive disease. If we assume that the reperfusion process was achieved at the time of SPECT examination, the hypothesis of "incomplete infarction"⁶⁷ should be reconsidered. A state of "elective emollition," a selective neuronal cell loss, was described by Scholz⁶⁸ in regions surrounding areas of complete infarction.⁶⁹ A significant correlation was found between reduced blood flow and neuronal loss in the cortex in animal experiments.^{59 70} Recent studies in animals⁷¹ gave some support to this hypothesis, although it remains under discussion.^{72 73} Acetazolamide and CO₂ challenge are useful in discriminating between diaschisis phenomenon or incomplete infarct and local exhausted cerebrovascular reserve.^{35 39 74} In case of diaschisis or incomplete infarction, the vasomotor reactivity is expected to be normal. The benzodiazepine receptor binding with ¹²³I-iomazenil, reflecting the neuronal cell viability after cerebral infarction, may have a role to play to differentiate hypoperfused areas due to incomplete infarct or diaschisis.^{75 76 77}

Thus, within the limits of our methodology, this study shows that SPECT is a more sensitive imaging technique than CT in detecting focal prolonged ischemia in TIAs. However, it does not provide additional clinically useful information on the vascular risk factors and etiology in consecutive patients. The clinical significance of such hypoperfusion should be further evaluated with vasoreactivity tests or more sensitive cameras in a larger population and in subgroups of patients. In the future we plan to study the outcome of TIA patients with a prolonged focal hypoperfusion.

	Selected Abbreviations and Acronyms

 

CITS = cerebral infarction with transient signs HMPAO = hexamethylpropyleneamine oxime rCBF = regional cerebral blood flow ROI = region of interest SPECT = single-photon emission CT TIA = transient ischemic attack

	Acknowledgments

 
The authors wish to thank Dr Christine Brichant, Brigitte Malhomme, and Christine László, who collected the data for the project.

Received September 19, 1995; revision received November 23, 1995; accepted December 5, 1995.

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