An Extravascular Component of Contrast Enhancement in Cranial Computed Tomography
•
Computed Tomography
Part II: Contrast Enhancement and the Blood-Tissue Barrier 1 Mokhtar H. Gado, M.D., Michael E. Phelps, Ph.D., and R. Edward Coleman, M.D.
The authors provide evidence of significant extravasation of contrast media responsible for the contrast enhancement of pathological tissue on computed tomography. The tissue-blood ratio of enhancement was calculated by the EMI scanner in 2 patients after injection of contrast material and prior to surgery; tumor-blood ratios for red blood cell and plasma tracers were calculated after surgery. The ratios of enhancement demonstrated the analogy between contrast enhancement and the leaking of radionuclide across the blood-brain barrier. This phenomenon may cause error if this technique is used for the measurement of cerebral blood volume. The area for complementary roles of CTand radionucJide brain imaging seems to be narrower than expected. INDEX TERMS:
•
Computed Tomography, cranial • Contrast media
Radiology 117:595-597, December 1975
HE DATA presented in Part I demonstrated extravasation of contrast media in pathological lesions but not in normal brain tissue. The mechanism of detecting lesions on radionuclide brain imaging is similar. We wish to compare the tissue-blood ratio of enhancement of pathological lesions in human subjects with the tissueblood ratios of a red blood cell (RBC) tracer (51Cr-RBC) and a plasma tracer, human serum albumin C25IHSA). We will then compare these data with those in a normal brain by studying the intracranial distribution of both tracers in an experimental animal.
blood ratio of 51Cr-RBC; (c) tumor-blood ratio of 1251HSA; and (d) the ratio of (c) to (b). A series of experiments on dogs were performed to determine the normal tissue-blood ratio of 51Cr-RBC and 1251_HSA. Four male dogs, each weighing approximately 20 kg, were injected intravenously with 250 jlCi of 1251HSA and 15 ml of 51Cr':'RBC (250 J,LCi). The animals were sacrificed 24 hours after the injection and samples of blood, muscle, brain, and dura were removed. The 51Cr and 1251 activity was measured for each sample and the number of counts/min.lg of sample was determined for each tracer. The tissue-blood ratio of each tracer was then calculated. The data collected for each animal consisted of: (a) tissue-blood ratio of 51Cr in brain tissue, dura, and muscle; (b) tissueblood ratio of 1251HSA in brain tissue, dura, and muscle; and (c) the ratio of (b) to (c) in brain tissue, dura, and muscle.
T
MATERIAL AND METHODS
In 2 patients being considered for the surgical removal of intracranial neoplasms, the histological diagnoses were proved to be pituitary adenoma and glioblastoma. Each patient had CCT scans before and after a 4-minute intravenous injection of 100 ml of iodinated contrast medium. Attenuation values of the lesion and of the corresponding blood samples were obtained; the tissueblood ratio of enhancement was then calculated as described in Part I. On the day prior to surgery, 250 jlCi of 1251HSA and 15 ml of the patient's blood, in which the red blood cells had been labeled with 51Cr (250 jlCi), were administered intravenously. At the time of surgery (24 hr. after injection), a portion of the tumor and a venous blood sample were taken and the activity of the 51Cr in each sample was measured with a sodium iodide scintillation detector. The activity of the 1251 was measured with a germanium semiconductor detector. The number of counts/min.lg of sample was determined for each tracer and the tumor-blood ratio of each tracer was then calculated. The data collected for each patient therefore consisted of: (a) tumor-blood ratio of enhancement by the EMI scanner; (b) tumor-
RESULTS
The data collected from the 2 patients with intracranial neoplasms are shown in TABLE I. The values of the tumor-blood ratio of contrast enhancement were 60.0 0k and 26.4% for the pituitary adenoma and glioblastoma, respectively. In both cases, these values were much higher than the values obtained with 51Cr_ RBC. The values of 1251HSA were more than 5 times the 51Cr-RBC values in each tumor. The tissue-blood ratios of 51Cr-RBC and 1251HSA in the brain, dura, and muscle of four normal experimental animals are shown in TABLE II. The values for 51Cr-RBC in the brain tissue varied from 1.1 % to 2.0%, with a mean of 1.5 %. The dura showed higher values, varying from 8.7% to 22.0% with a mean of 13.70/0. In the muscle, the values were similar to those of brain tissue,
1 From the Neuroradiology Section (M. H. G.), the Division of Radiation Sciences (M. E. P.), and the Division of Nuclear Medicine (R. E. C.), Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Mo. Accepted for publication in September 1975.
595
MOKHTAR H. GADO AND OTHERS MOKHTAR H. GADO AND OTHERS
596 596
Table I: Correlation of Contrast Enhancement and the Table I: Correlation of Contrast Enhancement the Albumin and Blood Spaces in Two Intracranial and Tumors Albumin and Blood Spaces in Two Intracranial Tumors Pituitary Pituitary Diagnosis Adenoma Glioblastoma Diagnosis Adenoma Glioblastoma Contrast Enhancement Contrast Enhancement (by EM I scanning) EM I scanning) of(by tumor 10.5 6.5 of 10.5 6.5 oftumor blood 17.5 24.6 of blood 17.5 24.6 tumor-blood ratio 60% 26.4% l251HSA and 5ICr-RBC tumor-blood ratio 60% 26.4% l251HSA and 5ICr-RBC studies studies tumor-blood ratio 10.1% 7.8% tumor-blood 10.1% 7.8% CICr-RBC) ratio CICr-RBC) ratio tumor-blood 52.4% 42.0% tumor-blood 52.4% 42.0% (l 251-RSA) ratio 251-RSA) (l ratio ( 1251-RSA) ( 1251-RSA) ratio 5.2/1 5.4/1 CS1Cr-RBC) ratio 5.2/1 5.4/1 CS1Cr-RBC) ratio
varying from 0.9% to 2.5% with a mean of 1.43%. varying from 0.9%ratios to 2.5% with ahowever, mean of showed 1.43%.a The tissue-blood of 1251HSA, The tissue-blood ratios of 1251HSA, however, showed a different pattern. In brain tissue the mean albumin value mean albumin value different pattern. In brain tissue the was 1.6 (±0.7) times the RBC value. In the dura a larger was 1.6albumin (±0.7) value times the value. 4.2 In the duratimes a larger mean wasRBC obtained: (±2.2) the mean albumin value was obtained: 4.2 (±2.2) times the RBC value. The largest albumin-blood value was found albumin-blood value was found RBC value. in The largest in muscle, which the mean was 8.8 (±6.5). in muscle, in which the mean was 8.8 (±6.5). DISCUSSION DISCUSSION
The data from the 2 patients with intracranial tumors The data from 2 patients with tumors indicate that thethetissue-blood ratiointracranial of enhancement indicate that the tissue-blood ratio of enhancement (60.0 % and 26.4 %) could not be explained by the in(60.0 % in andthe26.4 %) volume. could notUsing be explained the increase blood 51Cr-RBC,bythe blood crease in the blood volume. Using 51Cr-RBC, the blood volume in these tumors was found to be 10.1 % and was found to be % and volume in these tumors indicating that they were10.1 highly vas7.8 %, respectively, %, respectively, indicating that they were highly vas7.8 cular lesions (2-3 times the normal value). However, times the was normal However, cular lesions (2-3 the contrast enhancement 3 tovalue). 6 times greater the contrast enhancement was 3 to 6 times greater than the measured blood volume, which supports our than the measured volume, supports ratio our observation in Part Iblood that the values which of tissue-blood observation in Part Iwere that the values offor tissue-blood ratio unrealistic blood volume. of enhancement enhancement were unrealistic for blood volume. ofTherefore, the iodine responsible for the contrast enthe space. contrast enTherefore, responsible hancementthe wasiodine not confined to thefor blood hancement was not confined to the blood space. In both patients, the 1251_HSA tissue-blood ratio was In both patients, 1251_HSA tissue-blood ratio was approximately five the times that for 51Cr, confirming the approximately five times that for 51Cr, confirming theof presence of a defective blood-tissue barrier in each presence of a defective blood-tissue barrierexperiments in each of the two lesions. The data from our animal the twothat lesions. databrain fromthe our1251_HSA animal experiments show in the The normal tissue-blood show in the the 1251_HSA tissue-blood ratio that is only 1.6normal times brain the 51Cr tissue-blood ratio reratio is only 1.6 times the 51Cr tissue-blood ratio reflecting slight extravasation of albumin into the normal flecting slight extravasation of albumin into the normal brain tissue over a 24-hr. period. The low value of this overbrain a 24-hr. The low value this brain tissueperiod. compared to that in of muscle ratio tissue in normal normal brain tissue compared to that in muscle ratio in tissue is related to the phenomenon known as the tissue is related to the phenomenon known as the Table II: Tissue-Blood Ratios of 5ICr-RBC and l251-HSA Table II: Tissue-Blood RatiosinofFour 5ICr-RBC 0095*and l251-HSA in Normal Tissue in Normal Tissue in Four 0095* Brain Dura Muscle Brain Dura Muscle Tissue % 5ICr-RBC 1.5 ± 0.5 13.7 ± 5.8 1.4 ± 0.7 Tissue 1.5 ± 0.5 13.7 ± 5.8 1.4 ± 0.7 Blood % 5ICr-RBC Blood Tissue % 1251-RSA 2.1 ± 0.3 10.2 ± 6.4 49.3 ± 11.1 Tissue 2.1 ± 0.3 Blood % 1251-RSA 10.2 ± 6.4 49.3 ± 11.1 251-RSA) Blood (l ratio 1.6 ± 0.7 4.2 ± 2.2 8.8 ± 6.5 (l 251-RSA) ratio (SlCr-RBC) ratio 1.6 ± 0.7 4.2 ± 2.2 8.8 ± 6.5 (SlCr-RBC) ratio * Results, expressed as a mean ± 15.0. * Results, expressed as a mean ± 15.0.
December 1975 December 1975
"blood-brain barrier." In fact, the use of 1311HSA as a "blood-brain barrier." for In fact, the use ofof1311HSA as lea radiopharmaceutical the diagnosis cerebral radiopharmaceutical for the diagnosis of cerebral lesions in nuclear medicine has been dependent on the sions in nuclear medicine has been dependent on the 9/1 between the presence of a ratio of approximately 9/1 between the presence of a ratio of approximately lesion and the normal brain (1). The detection of lesions brain (1). The detection of lesions lesion and the normalalbumin of with radio-iodinated is related to the passage the passage of with radio-iodinated albumin is related to the tracer through a breakdown in the blood-brain bara breakdown in the blood-brain barthe riertracer and itsthrough distribution in a space larger than the blood rier and its distribution in a space larger than the blood space. space. A similarity between the distribution of the contrast between the distribution contrast A similarity medium and the tumor-blood ratios of of thethe 1251HSA exmedium and the tumor-blood ratios of the 1251HSA exists in the 2 patients studied. The phenomenon of conists in enhancement the 2 patients in studied. phenomenon con-to trast these The cases was mostlyofdue trast enhancement in these cases was mostly due to leaking of the iodinated contrast medium through a deleaking of the iodinated contrast medium through a defective blood-brain barrier to occupy a space 3 to 6 blood-brain occupy space 3 to 6 fective of the aenhancement of times that of blood. barrier A smalltopart part of the enhancement of times that of blood. A small these two tumors was also contributed to by the blood two tumors was also contributed to by the blood these volume (about 30 % and 20 %, respectively). volume (about 30 % and 20 %, respectively). The 4.2/1 ratio of the albumin value to the blood volratioofofthe theanimals albuminwas value to the bloodhigher volThein4.2/1 considerably ume the dura of the animals was considerably higher ume in the dura than the ratio in the brain tissue, indicating that in the the brain tissue, that barrier. in the than ratio in such function as aindicating blood-tissue dura the there is no such function as a blood-tissue barrier. dura there is no This also explains the enhancement of the falx often This also of the often Newton reported the falx opacificanoted on explains CCT (Fig.the 1).enhancement Newton reported the opacificanoted on CCT (Fig. 1). tion of the falx cerebri on cerebral angiography and also tion ofexcretory the falx cerebri on cerebral angiography and also after urography (2). after excretory urography (2). The evidence presented here and in Part I indicates Thepresence evidenceofpresented and in Part ofI indicates significanthere extravasation iodinated the of significant extravasation iodinated the presence comcontrast media into pathological tissue in of cranial comcontrast media into pathological tissueofinthese cranialdata puted tomography. The implications on puted tomography. The implications of these on of this technique in the evaluation of data cerebral the use in the evaluation of cerebral the use of this technique are evident. Such a phenomenon may hemodynamics are evident. Such a phenomenon may hemodynamics create sizable errors in measurement of the cerebral create sizable by errors in measurement the iscerebral blood volume this technique. Furtherofwork needed blood volume by this technique. Further work is needed relifor determining the kinetics of extravasation before the measurements kinetics of extravasation before relifor determining can be obtained. able blood volume can that be obtained. ableInblood volume the difference earlier studiesmeasurements (3) we suggested the difference In earlier studies (3) we suggested that between CCT and radionuclide brain imaging was esbetween and radionuclide imaging and was funcesbetweenbrain morphology sentially CCT the difference difference between morphology and funcsentially the tion, and anticipated complementary roles for CCT and complementary rolesdifference. for CCT and tion, and anticipated radionuclide brain imaging based on this Raradionuclide brain imaging based on this Ra-of has been related to difference. the function dionuclide imaging dionuclide imaging has been related to the function of
Fig. 1. Normal CCT scan of the slices above the level of the latFig.ventricles. 1. Normal scanintravenous of the slices above of thecontrast level ofmedium. the lateral A. CCT Before injection eral B. ventricles. A. Before intravenous injection of contrast medium. After contrast injection (note enhancement of the falx). B. After contrast injection (note enhancement of the falx).
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the blood-brain barrier. Our present results demonstrate the potential of CCT in evaluating the function of the blood-brain barrier by the phenomenon of contrast enhancement. The data indicate a similarity between the mechanism of contrast enhancement and the abnormal accumulation observed with radionuclide brain scanning. Additional studies are needed to better define the limits of this similarity and to better understand the kinetics of extravasation of the contrast medium. We have reviewed the first 1,220 CCT scans performed at our institute. Six hundred patients had both a radionuclide brain scan and a CCT scan performed within one week of each other. Of these, 59 had the CeT scan performed before and after the intravenous administration of 100 ml of iodinated contrast medium over a period of approximately 4 minutes. The eeT scans were analyzed for the presence or absence of abnormal accumulation. The correlation between the presence of contrast enhancement and abnormal radionuclide accumulation in the 59 patients is shown in TABLE III: there were 52 patients in whom the findings agreed. Enhancement and an abnormal radionuclide accumulation occurred in 34, and no enhancement occurred without abnormal radionuclide uptake in 18. There were only 7 in whom the findings did not concur. Of these, 2 showed contrast enhancement and a normal radionuclide brain scan. The locations of these lesions were in the suprasellar area (pituitary tumor) and brainstem (presumably glioma). The remaining 5 patients showed no contrast enhancement on CeT and an abnormal accumulation on the radionuclide brain scan. Each of them had a diagnosis of cerebral infarction. The apparent discrepancy in the cases of suprasellar and brainstem tumors can be explained by the location of the lesions. The detection of abnormal accumulation in these locations is known to be associated with difficulties arising from the superimposition of areas of normal accumulation at the base of the skull. However, with regard to the discrepancy in the 5 patients with cerebral infarction, it may be postulated that since cerebral infarction is the result of ischemia and impaired perfusion, there is slow "delivery" of the tracer. In radionuclide brain scanning, delayed imaging is associated with a higher frequency of abnormal studies. Using the present technique, eCT delayed imaging would not be expected to improve the delivery of the contrast agent because of competition from highly efficient renal clearance, which may decrease the amount of contrast medium below the detection limits of CCT scanning. Methods for improving this limitation are presently being investigated. With the exception of cases of cerebral infarction, a
Computed Tomography
597
CONTRAST ENHANCEMENT AND. THE BLOOD-TISSUE BARRIER
Table III: Correlation between CCT Contrast Enhancement and Abnormal Radionuclide Uptake in 59 Patients No Enhancement Enhancement Radionuclide positive negative Total
34 2* 36
5t 18 23
Total 39 20 59
* One pituitary tumor and on.e brainstem tumor. t .A.I! five cases were cerebral infarcts. strong correlation exists between CTT contrast enhancement and conventional radionuclide brain imaging. If further work supports these observations, the previous distinction between these techniques may have to be revised; the scope for complementary roles of the two procedures may be narrower than previously anticipated. CONCLUSIONS
Contrast enhancement in tumors depends to a significant extent on extravasation of contrast medium at the blood-brain barrier; the portion contributed by increased vascularity can be determined only by blood volume measurements. It is expected, however, that an increase in blood volume augments such extravasation by increasing the amount of contrast medium delivered to the site of the defective blood-brain barrier. The two main implications of these observations are: (a) there are potential difficulties in the use of contrast enhancement for measurements of cerebral hemodynamics; and (b) the area for complementary roles of CT and conventional radionuclide brain imaging seems to be narrower than expected. Department of Neuroradiology Mallinckrodt Institute of Radiology Washington University School of Medicine 510 S. Kingshighway St. Louis, Mo. 63110 REFERENCES 1. Burrows EH: The clinical utility of brain scanning in nuclear medicine. [In] Potchen EG, McCready VR, ed, Progress in Nuclear Medicine. Baltimore, Md., University Park Press, 1972, pp 287-335 2. Newton TH, Gooding CA, Price DC: Opacification of falx and tentorium during cerebral angiography: preliminary report. Invest Radiol 5:348-354, Sep-Oct 1970 3. Gado M, Coleman RE, Alderson PO: Comparison of computerized transaxial tomography and radionuclide imaging of the central nervous system. [In] de Blanc HH, Sorenson J, ed, The Past, Present and Future of Non-Invasive Brain Imaging. Society of Nuclear Medicine (to be published)
•
Computed Tomography
Part II: Contrast Enhancement and the Blood-Tissue Barrier 1 Mokhtar H. Gado, M.D., Michael E. Phelps, Ph.D., and R. Edward Coleman, M.D.
The authors provide evidence of significant extravasation of contrast media responsible for the contrast enhancement of pathological tissue on computed tomography. The tissue-blood ratio of enhancement was calculated by the EMI scanner in 2 patients after injection of contrast material and prior to surgery; tumor-blood ratios for red blood cell and plasma tracers were calculated after surgery. The ratios of enhancement demonstrated the analogy between contrast enhancement and the leaking of radionuclide across the blood-brain barrier. This phenomenon may cause error if this technique is used for the measurement of cerebral blood volume. The area for complementary roles of CTand radionucJide brain imaging seems to be narrower than expected. INDEX TERMS:
•
Computed Tomography, cranial • Contrast media
Radiology 117:595-597, December 1975
HE DATA presented in Part I demonstrated extravasation of contrast media in pathological lesions but not in normal brain tissue. The mechanism of detecting lesions on radionuclide brain imaging is similar. We wish to compare the tissue-blood ratio of enhancement of pathological lesions in human subjects with the tissueblood ratios of a red blood cell (RBC) tracer (51Cr-RBC) and a plasma tracer, human serum albumin C25IHSA). We will then compare these data with those in a normal brain by studying the intracranial distribution of both tracers in an experimental animal.
blood ratio of 51Cr-RBC; (c) tumor-blood ratio of 1251HSA; and (d) the ratio of (c) to (b). A series of experiments on dogs were performed to determine the normal tissue-blood ratio of 51Cr-RBC and 1251_HSA. Four male dogs, each weighing approximately 20 kg, were injected intravenously with 250 jlCi of 1251HSA and 15 ml of 51Cr':'RBC (250 J,LCi). The animals were sacrificed 24 hours after the injection and samples of blood, muscle, brain, and dura were removed. The 51Cr and 1251 activity was measured for each sample and the number of counts/min.lg of sample was determined for each tracer. The tissue-blood ratio of each tracer was then calculated. The data collected for each animal consisted of: (a) tissue-blood ratio of 51Cr in brain tissue, dura, and muscle; (b) tissueblood ratio of 1251HSA in brain tissue, dura, and muscle; and (c) the ratio of (b) to (c) in brain tissue, dura, and muscle.
T
MATERIAL AND METHODS
In 2 patients being considered for the surgical removal of intracranial neoplasms, the histological diagnoses were proved to be pituitary adenoma and glioblastoma. Each patient had CCT scans before and after a 4-minute intravenous injection of 100 ml of iodinated contrast medium. Attenuation values of the lesion and of the corresponding blood samples were obtained; the tissueblood ratio of enhancement was then calculated as described in Part I. On the day prior to surgery, 250 jlCi of 1251HSA and 15 ml of the patient's blood, in which the red blood cells had been labeled with 51Cr (250 jlCi), were administered intravenously. At the time of surgery (24 hr. after injection), a portion of the tumor and a venous blood sample were taken and the activity of the 51Cr in each sample was measured with a sodium iodide scintillation detector. The activity of the 1251 was measured with a germanium semiconductor detector. The number of counts/min.lg of sample was determined for each tracer and the tumor-blood ratio of each tracer was then calculated. The data collected for each patient therefore consisted of: (a) tumor-blood ratio of enhancement by the EMI scanner; (b) tumor-
RESULTS
The data collected from the 2 patients with intracranial neoplasms are shown in TABLE I. The values of the tumor-blood ratio of contrast enhancement were 60.0 0k and 26.4% for the pituitary adenoma and glioblastoma, respectively. In both cases, these values were much higher than the values obtained with 51Cr_ RBC. The values of 1251HSA were more than 5 times the 51Cr-RBC values in each tumor. The tissue-blood ratios of 51Cr-RBC and 1251HSA in the brain, dura, and muscle of four normal experimental animals are shown in TABLE II. The values for 51Cr-RBC in the brain tissue varied from 1.1 % to 2.0%, with a mean of 1.5 %. The dura showed higher values, varying from 8.7% to 22.0% with a mean of 13.70/0. In the muscle, the values were similar to those of brain tissue,
1 From the Neuroradiology Section (M. H. G.), the Division of Radiation Sciences (M. E. P.), and the Division of Nuclear Medicine (R. E. C.), Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Mo. Accepted for publication in September 1975.
595
MOKHTAR H. GADO AND OTHERS MOKHTAR H. GADO AND OTHERS
596 596
Table I: Correlation of Contrast Enhancement and the Table I: Correlation of Contrast Enhancement the Albumin and Blood Spaces in Two Intracranial and Tumors Albumin and Blood Spaces in Two Intracranial Tumors Pituitary Pituitary Diagnosis Adenoma Glioblastoma Diagnosis Adenoma Glioblastoma Contrast Enhancement Contrast Enhancement (by EM I scanning) EM I scanning) of(by tumor 10.5 6.5 of 10.5 6.5 oftumor blood 17.5 24.6 of blood 17.5 24.6 tumor-blood ratio 60% 26.4% l251HSA and 5ICr-RBC tumor-blood ratio 60% 26.4% l251HSA and 5ICr-RBC studies studies tumor-blood ratio 10.1% 7.8% tumor-blood 10.1% 7.8% CICr-RBC) ratio CICr-RBC) ratio tumor-blood 52.4% 42.0% tumor-blood 52.4% 42.0% (l 251-RSA) ratio 251-RSA) (l ratio ( 1251-RSA) ( 1251-RSA) ratio 5.2/1 5.4/1 CS1Cr-RBC) ratio 5.2/1 5.4/1 CS1Cr-RBC) ratio
varying from 0.9% to 2.5% with a mean of 1.43%. varying from 0.9%ratios to 2.5% with ahowever, mean of showed 1.43%.a The tissue-blood of 1251HSA, The tissue-blood ratios of 1251HSA, however, showed a different pattern. In brain tissue the mean albumin value mean albumin value different pattern. In brain tissue the was 1.6 (±0.7) times the RBC value. In the dura a larger was 1.6albumin (±0.7) value times the value. 4.2 In the duratimes a larger mean wasRBC obtained: (±2.2) the mean albumin value was obtained: 4.2 (±2.2) times the RBC value. The largest albumin-blood value was found albumin-blood value was found RBC value. in The largest in muscle, which the mean was 8.8 (±6.5). in muscle, in which the mean was 8.8 (±6.5). DISCUSSION DISCUSSION
The data from the 2 patients with intracranial tumors The data from 2 patients with tumors indicate that thethetissue-blood ratiointracranial of enhancement indicate that the tissue-blood ratio of enhancement (60.0 % and 26.4 %) could not be explained by the in(60.0 % in andthe26.4 %) volume. could notUsing be explained the increase blood 51Cr-RBC,bythe blood crease in the blood volume. Using 51Cr-RBC, the blood volume in these tumors was found to be 10.1 % and was found to be % and volume in these tumors indicating that they were10.1 highly vas7.8 %, respectively, %, respectively, indicating that they were highly vas7.8 cular lesions (2-3 times the normal value). However, times the was normal However, cular lesions (2-3 the contrast enhancement 3 tovalue). 6 times greater the contrast enhancement was 3 to 6 times greater than the measured blood volume, which supports our than the measured volume, supports ratio our observation in Part Iblood that the values which of tissue-blood observation in Part Iwere that the values offor tissue-blood ratio unrealistic blood volume. of enhancement enhancement were unrealistic for blood volume. ofTherefore, the iodine responsible for the contrast enthe space. contrast enTherefore, responsible hancementthe wasiodine not confined to thefor blood hancement was not confined to the blood space. In both patients, the 1251_HSA tissue-blood ratio was In both patients, 1251_HSA tissue-blood ratio was approximately five the times that for 51Cr, confirming the approximately five times that for 51Cr, confirming theof presence of a defective blood-tissue barrier in each presence of a defective blood-tissue barrierexperiments in each of the two lesions. The data from our animal the twothat lesions. databrain fromthe our1251_HSA animal experiments show in the The normal tissue-blood show in the the 1251_HSA tissue-blood ratio that is only 1.6normal times brain the 51Cr tissue-blood ratio reratio is only 1.6 times the 51Cr tissue-blood ratio reflecting slight extravasation of albumin into the normal flecting slight extravasation of albumin into the normal brain tissue over a 24-hr. period. The low value of this overbrain a 24-hr. The low value this brain tissueperiod. compared to that in of muscle ratio tissue in normal normal brain tissue compared to that in muscle ratio in tissue is related to the phenomenon known as the tissue is related to the phenomenon known as the Table II: Tissue-Blood Ratios of 5ICr-RBC and l251-HSA Table II: Tissue-Blood RatiosinofFour 5ICr-RBC 0095*and l251-HSA in Normal Tissue in Normal Tissue in Four 0095* Brain Dura Muscle Brain Dura Muscle Tissue % 5ICr-RBC 1.5 ± 0.5 13.7 ± 5.8 1.4 ± 0.7 Tissue 1.5 ± 0.5 13.7 ± 5.8 1.4 ± 0.7 Blood % 5ICr-RBC Blood Tissue % 1251-RSA 2.1 ± 0.3 10.2 ± 6.4 49.3 ± 11.1 Tissue 2.1 ± 0.3 Blood % 1251-RSA 10.2 ± 6.4 49.3 ± 11.1 251-RSA) Blood (l ratio 1.6 ± 0.7 4.2 ± 2.2 8.8 ± 6.5 (l 251-RSA) ratio (SlCr-RBC) ratio 1.6 ± 0.7 4.2 ± 2.2 8.8 ± 6.5 (SlCr-RBC) ratio * Results, expressed as a mean ± 15.0. * Results, expressed as a mean ± 15.0.
December 1975 December 1975
"blood-brain barrier." In fact, the use of 1311HSA as a "blood-brain barrier." for In fact, the use ofof1311HSA as lea radiopharmaceutical the diagnosis cerebral radiopharmaceutical for the diagnosis of cerebral lesions in nuclear medicine has been dependent on the sions in nuclear medicine has been dependent on the 9/1 between the presence of a ratio of approximately 9/1 between the presence of a ratio of approximately lesion and the normal brain (1). The detection of lesions brain (1). The detection of lesions lesion and the normalalbumin of with radio-iodinated is related to the passage the passage of with radio-iodinated albumin is related to the tracer through a breakdown in the blood-brain bara breakdown in the blood-brain barthe riertracer and itsthrough distribution in a space larger than the blood rier and its distribution in a space larger than the blood space. space. A similarity between the distribution of the contrast between the distribution contrast A similarity medium and the tumor-blood ratios of of thethe 1251HSA exmedium and the tumor-blood ratios of the 1251HSA exists in the 2 patients studied. The phenomenon of conists in enhancement the 2 patients in studied. phenomenon con-to trast these The cases was mostlyofdue trast enhancement in these cases was mostly due to leaking of the iodinated contrast medium through a deleaking of the iodinated contrast medium through a defective blood-brain barrier to occupy a space 3 to 6 blood-brain occupy space 3 to 6 fective of the aenhancement of times that of blood. barrier A smalltopart part of the enhancement of times that of blood. A small these two tumors was also contributed to by the blood two tumors was also contributed to by the blood these volume (about 30 % and 20 %, respectively). volume (about 30 % and 20 %, respectively). The 4.2/1 ratio of the albumin value to the blood volratioofofthe theanimals albuminwas value to the bloodhigher volThein4.2/1 considerably ume the dura of the animals was considerably higher ume in the dura than the ratio in the brain tissue, indicating that in the the brain tissue, that barrier. in the than ratio in such function as aindicating blood-tissue dura the there is no such function as a blood-tissue barrier. dura there is no This also explains the enhancement of the falx often This also of the often Newton reported the falx opacificanoted on explains CCT (Fig.the 1).enhancement Newton reported the opacificanoted on CCT (Fig. 1). tion of the falx cerebri on cerebral angiography and also tion ofexcretory the falx cerebri on cerebral angiography and also after urography (2). after excretory urography (2). The evidence presented here and in Part I indicates Thepresence evidenceofpresented and in Part ofI indicates significanthere extravasation iodinated the of significant extravasation iodinated the presence comcontrast media into pathological tissue in of cranial comcontrast media into pathological tissueofinthese cranialdata puted tomography. The implications on puted tomography. The implications of these on of this technique in the evaluation of data cerebral the use in the evaluation of cerebral the use of this technique are evident. Such a phenomenon may hemodynamics are evident. Such a phenomenon may hemodynamics create sizable errors in measurement of the cerebral create sizable by errors in measurement the iscerebral blood volume this technique. Furtherofwork needed blood volume by this technique. Further work is needed relifor determining the kinetics of extravasation before the measurements kinetics of extravasation before relifor determining can be obtained. able blood volume can that be obtained. ableInblood volume the difference earlier studiesmeasurements (3) we suggested the difference In earlier studies (3) we suggested that between CCT and radionuclide brain imaging was esbetween and radionuclide imaging and was funcesbetweenbrain morphology sentially CCT the difference difference between morphology and funcsentially the tion, and anticipated complementary roles for CCT and complementary rolesdifference. for CCT and tion, and anticipated radionuclide brain imaging based on this Raradionuclide brain imaging based on this Ra-of has been related to difference. the function dionuclide imaging dionuclide imaging has been related to the function of
Fig. 1. Normal CCT scan of the slices above the level of the latFig.ventricles. 1. Normal scanintravenous of the slices above of thecontrast level ofmedium. the lateral A. CCT Before injection eral B. ventricles. A. Before intravenous injection of contrast medium. After contrast injection (note enhancement of the falx). B. After contrast injection (note enhancement of the falx).
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the blood-brain barrier. Our present results demonstrate the potential of CCT in evaluating the function of the blood-brain barrier by the phenomenon of contrast enhancement. The data indicate a similarity between the mechanism of contrast enhancement and the abnormal accumulation observed with radionuclide brain scanning. Additional studies are needed to better define the limits of this similarity and to better understand the kinetics of extravasation of the contrast medium. We have reviewed the first 1,220 CCT scans performed at our institute. Six hundred patients had both a radionuclide brain scan and a CCT scan performed within one week of each other. Of these, 59 had the CeT scan performed before and after the intravenous administration of 100 ml of iodinated contrast medium over a period of approximately 4 minutes. The eeT scans were analyzed for the presence or absence of abnormal accumulation. The correlation between the presence of contrast enhancement and abnormal radionuclide accumulation in the 59 patients is shown in TABLE III: there were 52 patients in whom the findings agreed. Enhancement and an abnormal radionuclide accumulation occurred in 34, and no enhancement occurred without abnormal radionuclide uptake in 18. There were only 7 in whom the findings did not concur. Of these, 2 showed contrast enhancement and a normal radionuclide brain scan. The locations of these lesions were in the suprasellar area (pituitary tumor) and brainstem (presumably glioma). The remaining 5 patients showed no contrast enhancement on CeT and an abnormal accumulation on the radionuclide brain scan. Each of them had a diagnosis of cerebral infarction. The apparent discrepancy in the cases of suprasellar and brainstem tumors can be explained by the location of the lesions. The detection of abnormal accumulation in these locations is known to be associated with difficulties arising from the superimposition of areas of normal accumulation at the base of the skull. However, with regard to the discrepancy in the 5 patients with cerebral infarction, it may be postulated that since cerebral infarction is the result of ischemia and impaired perfusion, there is slow "delivery" of the tracer. In radionuclide brain scanning, delayed imaging is associated with a higher frequency of abnormal studies. Using the present technique, eCT delayed imaging would not be expected to improve the delivery of the contrast agent because of competition from highly efficient renal clearance, which may decrease the amount of contrast medium below the detection limits of CCT scanning. Methods for improving this limitation are presently being investigated. With the exception of cases of cerebral infarction, a
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CONTRAST ENHANCEMENT AND. THE BLOOD-TISSUE BARRIER
Table III: Correlation between CCT Contrast Enhancement and Abnormal Radionuclide Uptake in 59 Patients No Enhancement Enhancement Radionuclide positive negative Total
34 2* 36
5t 18 23
Total 39 20 59
* One pituitary tumor and on.e brainstem tumor. t .A.I! five cases were cerebral infarcts. strong correlation exists between CTT contrast enhancement and conventional radionuclide brain imaging. If further work supports these observations, the previous distinction between these techniques may have to be revised; the scope for complementary roles of the two procedures may be narrower than previously anticipated. CONCLUSIONS
Contrast enhancement in tumors depends to a significant extent on extravasation of contrast medium at the blood-brain barrier; the portion contributed by increased vascularity can be determined only by blood volume measurements. It is expected, however, that an increase in blood volume augments such extravasation by increasing the amount of contrast medium delivered to the site of the defective blood-brain barrier. The two main implications of these observations are: (a) there are potential difficulties in the use of contrast enhancement for measurements of cerebral hemodynamics; and (b) the area for complementary roles of CT and conventional radionuclide brain imaging seems to be narrower than expected. Department of Neuroradiology Mallinckrodt Institute of Radiology Washington University School of Medicine 510 S. Kingshighway St. Louis, Mo. 63110 REFERENCES 1. Burrows EH: The clinical utility of brain scanning in nuclear medicine. [In] Potchen EG, McCready VR, ed, Progress in Nuclear Medicine. Baltimore, Md., University Park Press, 1972, pp 287-335 2. Newton TH, Gooding CA, Price DC: Opacification of falx and tentorium during cerebral angiography: preliminary report. Invest Radiol 5:348-354, Sep-Oct 1970 3. Gado M, Coleman RE, Alderson PO: Comparison of computerized transaxial tomography and radionuclide imaging of the central nervous system. [In] de Blanc HH, Sorenson J, ed, The Past, Present and Future of Non-Invasive Brain Imaging. Society of Nuclear Medicine (to be published)
