Occlusion of the internal carotid artery (ICA) is oneof thecommoncausesof stroke,andin patientswithcerebrovascular symptoms, nine percent were found tohave an occlusion ofthe ICA at autopsy (1). Ofthe patients who died of stroke, 19% were found to have anocclusion of the ICA (2). Various methods, such as arteriography (3,4), madionuclide angiography (5,6), orultrasonography (7—9)etc, have been applied to the diagnosis of ICA occlusion or the assessment of collateralcirculation.

Meanwhile, in the field of nuclear medicine, madiolabeled human albumin microspheres (HAM), originallyused in lung perfusion studies, have additional applications in the evaluation of brain blood flow (10—12) and

are said to be more efficient than pertechnetate scanning(1 1). However, previous studies concerned with particulate cerebral perfusion imaging have used singly labeledparticles such as Ic-99m HAM (I 1—13)or I-i 31 MAA(/4).

Received Mar. 1, 1982; revision accepted May 10, 1982.

For reprints contact: Hideki Etani, Div.ofNuclear Medicine,OsakaUniv. Med. School, Fukushima, I chome, Fukushima-ku, Osaka 553,Japan.

The purpose of the present paper is to be describe anew method of cerebral perfusion imaging with twotracers concurrently (Tc-99m- and In-i 11-labeledHAMs) and the clinical application of this method forthe diagnosis and assessment of the collateral circulationpattern in patients with ICA occlusion.

MATERIALS

We examined i 5 patients with evidence of cerebrovascular disease, in whom the diagnosis of a unilateralICA occlusion was subsequently confirmed by angiogmaphy.The ages ranged from 47 to 75, with mean age61.9. Clinicalmanifestationswere:transientischemicattacks (hAs) in five cases, minor stroke in three, andcomplete stroke in seven.

METHODS

Preparation of labeled HAMs. In-i 11 HAMs (diam15 ±5 zm)werepreparedessentiallyaccordingto themethod of Hagan et al. (15). The procedure was to add1ml of 10%sodiumacetateand4mlof In-i 11chloride

Volume 23, Number 9 823

CerebralPerfusionImagingwfthAlbuminMicrospheresTaggedwilli Tc-99m

andIn—111 inCaseswithInternalCarotidOcclusion

Hideki Etani, Kazufumi Kimisa, Shotaro Yoneda, Yoshiyasu Isuda, YoshmnariIsaka, Masaichi Nakamura,andTsutomuAsai

Osaka University Medical School, Fukushima, 1.chorne,Fukushima-ku, Osaka 553, Japan

Cerebralperfusionimagingwfthdual-tracer(Tc-99mandIn-I I 1) humanalbummmicrosphores(HAMscintigraphy)wasperformedin 15caseswithunilateralocclusionof the internalcarotidartery,for thediagnosisandevaluationof collatorai circulationpatterns.AfterinjectionofTc-99mmicrosphorosintoonecommoncarotidarteryandIn-I11 HAMSIntotheother,twoperfusionimages,oneforeachcarotidartery,wereclearlydifferentiatedbyappropriatepulse-heightdiscrimination.Withthismethod,diagnosisof internalcarotidarteryocclusionwasdefinftelymadeineightpatients,suspectedinsix,andmissedinone.Thecollateralperfusionareas from the contraiateralICA and ipsliateralexternal carotidartery worewelldemonstratedbythismethod,andthescintigraphicresultsagreedwellwiththe angiographic findings in all cass. Dual-tracer HAM scintigraphy is capable ofadding information about coiiaterais at the capillary level to the anatomic information obtainedby angiography.

J Nuci Med 23: 823—829, 1982

ETANI, KIMURA, YONEDA,TSUDA, ISAKA, NAKAMURA,ASAI

(3 mCi) in 0.05N HC1to a vial containingHAMs(400,000particles)soakedwithstannouschloride.Thevial was briefly sonicated, then immersed in a boilingwater bath for 5 mm and cooled in an operating ultrasonic water bath. The mixture was then centrifuged andthe supemnatant discarded. The sediment (labeledHAMs) was resuspended in 5 ml ofsaline solution contaming 0.05% of Tween 80 and sonicated for 5 mm. The

labeling efficiency was 92%.Tc-99m-labeled HAMs were prepared by adding 1 ml

of saline solution containing pertechnetate (iS mCi) intoa vial containing HAMs (400,000 particles) soaked withstannous chloride. The vial was shaken vigorously for tenseconds, then immersed in a water bath and exposed toultrasound for 5 mm. The mixture was then centrifugedand the supernatent discarded. The sediment (labeledHAMs) was resuspended in 5 ml ofsaline solution contaming 0.05% of Iween 80, then sonicated for 5 mm. Thelabeling efficacy was 95%.

The size, shape, and lack of clumping were checkedmicroscopically.

Injection and imaging technique. Approximately80,000particles(3 mCi) of Ic-99m-labeledHAMs in1 ml of saline solution were injected slowly upstream for30secintoonecommoncarotidartery(CCA),andapproximately 80,000 particles of In- 111 HAMs (600 tCi)were injected in the same way into the other CCA. Theprocedure was done without catheterization, using aglass syringe and 23-gauge needle. Scintigmaphy wasstarted within 20 mm after the injection of the tracer. Allimages were obtained with a gamma camera and a medium-energy collimator. The energy peak at 173 keV wasused for In-I 11 and that at 140 keV for Ic-99m, with10%symmetricalwindowsforboth.Anterior,vertex,andlateral views were obtained for Tc-99m and In-i 11. Thecalculated downscatter from the 247-keV gamma intothe 173-keV window, and from those two gammas intothe l40-keV window, was found to be

ARTERY@adeFilling

of the cerebral arteries on thePerfusion area on the HAMHAMscintigramoccludedside viaanteriorscintigramcommunicating

arteryfromcontralateral

ICA on theangiogram(—)No

fillingof cerebral arteries of theCCA territory on thecontralateraloccludedsideside\@

$(+)ACA

onthe occludedsideContralateral CCAterritoryandipsilateral ACAterritory;@(++)ACA

and a few branchesof MCA onContralateral CCA territoryandtheoccluded sideipsilateral ACA and a part of MCA

territory@______ \\@@

TABLE 2. EXTENT OF COLLATERALCIRCULATION FROM IPSILATERAL EXTERNALCAROTIDARTERY@adeFilling

of the cerebral arteries on theoccluded side via ECAon theangiogramPerfusion

area on the HAMscintigramHAM

scintigram(—)No

fillingof cerebralarteriesontheoccluded sideOnly

ECAterritory(.‘T:'m:@(+)A

few branches of MCA on theoccluded sideECA

territory and a part of MCAterritory-

PRELIMINARY NOTES

TABLE 1. EXTENT OF COLLATERALCIRCULATION FROM CONTRALATERALINTERNAL CAROTID

(+++) ACA and almost all MCA branchesontheoccludedside

Contralateral CCA territory and

ipsilateralACAandalmostallMCAterritory

CCA:commoncarotidartery,ICA:Internalcarotidartery,ACA:anteriorcerebralartery,MCA:middlecerebralartery.

[Table 2, grade (—)],and was suspected in six patients,with poor collateral circulation from the ipsilateral ECA[Table 2, grade (+), Cases 3, 4, 6—8,13] . The diagnosisof ICA occlusion was missed, however, in one patientwith good collateral circulation from ipsilateral ECA[Table 2, grade (+4-), Case 2].

In 15 cases with ICA occlusion, dual-tracer HAMscintigraphy allowed the evaluation of the collateralcirculation pattern from the contmalatemalICA and fromthe ipsilateral ECA (Table 3). Fomexample, Fig. 2 showsthe scintigrams of Case 10, with right ICA occlusion.Ic-99m HAMs were injected into the right CCA and

(++) Almost all MCA branches on theoccluded side

ECAterrftory and almost all MCAterritory

MCA: middle cerebral artery, ECA:external carotid artery.

Volume 23, Number 9 825

Collateralcirculationpattern'CaseClinicalFrom

I- FromC-No.AgeSex diagnosisECAt 1CM

—

ETANI, KIMURA, YONEDA,TSUDA, ISAKA, NAKAMURA,ASAI

TABLE3. CASE SUMMARYANDSCINTIGRAPHICRESULTSOF COLLATERAL

CIRCULATIONPATIERN A

64 Male Completedstroke

2 68 Male Completedstroke

3 58 Male Completedstroke

4 63 Male TIAs@5 47 Male Completed

stroke6 53 Male TIA7 63 Male Minorstroke8 75 Male Completed

stroke9 71 Male Minor stroke

10 68 Male hA11 47 Male Minor stroke12 72 Male Completed

stroke13 53 Male TIA14 63 FemaleTIA15 64 Male Completed

stroke

. The grades of collateral circulation pattern in HAM

scintigraphycoinc@edwith those from angiographyin eachcase.

t l-ECA; Collateral circulation from ipsilateral externalcarotid artery.

t C-ICA; Collateral cfrculation from contralateral internalcarotid artery.

§TIA= transientischemicattacks.

In-I 11 HAMs into the left. In the Ic-99m HAM scmtigrams, activity was found only in the ECA territory, andnone in that of the ICA. In the In-l 11HAM scintigrams,the activity was detected in the territories of right antenor cerebral artery (ACA) and middle cerebral artery(MCA) as well as in that of the left CCA. The scintigrams showed the patient to have good collateral circulation from the contralatemal ICA through the anteriorcommunicating artery, but no collateral from the ipsilateral ECA, and these findings agreed well with theangiogmams (Fig. 2, 3). Figure 4 shows the scintigramsof Case 2, with left ICA occlusion. Ic-99m HAMs wereinjected into the mightCCA and In-i 11 HAMs into theleft. In the In-l I 1 HAM scintigrams, activity was detected in the territories of the MCA and the ECA. In theIc-99m HAM scintigrams, the activity was detected inthe territories of the left ACA and the right CCA. Thefindings indicated good collateral circulation from the

1'@++ +

+

+— ++

+ +++ +++ ++

—

— +++— +

— ++

+ +—

— +++

B

Tc-99m.HAM In—ill-HAM@

C D

Tc—99m-HAM— In—111HAM@FIG.2. Anterior(A),vertex(B),rightlateral(C),andleftlateral(D)scintigrams in Case 10,with right ICAocclusion.Nocollateral fromipsilateral ECA,and good collateral from opposite ICA.

ipsilateral ECA and poor collateral from the oppositeICA, findings that agreed well with those of the angiograms (Figs. 4, 5).

Collateral circulation from a contralatemal ICA waswell defined in the vertex and anterior views, and thatfrom ipsilatemalECA was well defined in the lateral view.From the scintigrams, the extent of collateral circulationfrom the opposite ICA varied from none to good for theterritory of the ACA and almost all of the MCA, and

that from the ipsilateral ECA varied from none to goodfor almost all of the territory of the MCA (Table 3). Thescintigraphic results for the collateral circulation patternagreed well with the angiographic findings, and indicatedregional flow even more precisely, as a perfusion area,

in each case.

826 THE JOURNAL OF NUCLEAR MEDICINE

PRELIMINARY NOTES

A

( .@i..'

BTc-99mHAM In-@111-HAM@

Tc—99m'HAM@ In—ill-HAM@FIG.4. Anterior(A),vertex(B),rightlateral(C),andleftlateral(0)scintigrams in Case2, with left ICAocclusion.Goodcollateral fromipsilateral ECAand poor collateral from opposite ICA.

FIG. 3. Patient of Fig. 2. Right carotid angiography (A)showed ri@itICA occlusion(whitearrow)andno collateralfrom ECA.Left carotidangiography (B) showed good collateral from the opposite ICAthroughanteriorcommunicatingartery.

COMPLICATIONS

None of the patients showed any clinical complications, such as ischemic neurologic attack, seizure, distumbance of consciousness or aggravation of existingneurologic deficits, either during or after the procedure.Neither were abnormal electroencephalographic findingsobserved.

DISCUSSION

The intracarotid injection of radioactive microsphemesfor brain scintigraphy offers a sensitive method of determining relative regional cerebral blood flow (11—13).

The injected microsphemes are temporarily trapped inthe micmovasculatumeand distributed in proportion toregional blood flow.

In animal experiments, the intracarotid injection ofradioactive albumin microsphemes and macroaggregatesof albumin failed to produce gross pathologic or microscopic alteration in the brain in spite ofdoses 5—500times(10), 5—10times (16), or 10—30times (17) the proteindose used in human studies. The intracamotid injectionof limited dosesof smallparticles(under40 jzm) hasfailed to show deleterious effects (10,17). The specificrisk related to injection of microspheres is the exceptionalincidence of an anaphylactoid reaction (/8). Likewise,the intracoronamy injection of radiolabeled particles wasreported to be safe if the size and numbers of the particleswere adequately controlled (/9).

In our study, the time required for the procedure ofinjection of the tracer into the CCA with a glass syringeand 23-gauge needle, was one minute or less, and becausecatheterization is not necessary, bleeding can easily be

controlled with forefinger pressure for a few minutes.This procedure, therefore, is simpler and less invasivethan angiography. An important difference betweenHAM scintigraphy and angiography is that the formercauses less physiological disturbance: the injected ma

C D

FIG.5. PatientofFig.4.Leftcarotidangipgraphy(B)showedleftICA occlusion (white arrow) and collateral from ipsilateral ECAthrough ophthalmic artery. Right carotid angiography(A) showedpoorcollateralfromoppositeICA.

827Volume 23, Number 9

ETANI, KIMURA, YONEDA, TSUDA, ISAKA, NAKAMURA,ASAI

temial is small in volume and injection pressure is low.However, the main drawback of the dual-tracermethod—even with a small volume of labeled microsphere and without catheterization—is the necessity forbilateral carotid puncture. We have observed no adversereactions during our limited experience with 40 patients,including 15 cases with ICA occlusion; there may onlybe unforeseen hazards, evident only after more patientsare studied and longer followup is obtained.

The application of particulate imaging for brainscintigraphy has been reported with single-tracer labeling, such as Ic-99m HAM(1 1—13),or I-13iMAA(l4). In the single-labeled technique, scintigraphyofonly the cerebral hemisphere on the side ofthe injectedcarotid is possible, so in order to obtain bilateral information, the patient must be studied again on another

day, or the aortic arch or left ventricle injected. Theformer is time-consuming and the latter requires cathetemization, and the blood flows of the separate carotidarteries cannot be obtained. However, by using thedual-tracer method described here, scintigraphy of bothhemispheres and the blood distribution of each carotidartery can be demonstrated at the same time in oneprocedure. When each carotid receives microsphemeswith its own specific label, two separate perfusion imagescan be clearly differentiated by pulse-height discnimination, and the method is suitable for clinical use. Thedual-tracer method has the advantages of good imageresolution, the potential to indicate the regional blooddistribution fmomeach carotid artery individually, andthe ability to assess the collateral circulation pattern. Incases with ICA occlusion, the dual-tracer method isespecially useful in evaluating the collateral circulationpattern from the opposite ICA and the ipsilateral ECA.The grading of collateral circulation via the anteriorcommunicating artery might depend on the dominanceof this vessel and its contribution to flow in a given individual. Similarly, collateral flow via ophthalmic arteryand ECA shows significant variations between individuals. At present, cerebral angiography is the most important diagnostic examination, and the ability to makea definite diagnosis by the dual-tracer method is less

certain, so the latter method alone is now of limited use,such as in a smaller community hospital or one withoutcerebral angiographic facilities. Even granted a hospitalwith angiographic facilities however, this dual-tracermethod, performed in conjunction with angiography,may be capable of adding supplemental physiologicalinformation about collatemalsat the capillary level to theanatomic information obtained by angiography. Thedual-tracer method will be also suitable for followupstudy in patients with ICA occlusion who were treatedby anastomosis between external and internal carotids,to determine the patency of the bypass. In addition, ourpreliminary results showed that this method was also

useful for the assessment of cerebral blood flow with a

bilateral hemispheric lesion, such as in multiple cerebralinfarction, or Binswanger's dementia.

From the investigative point of view, cerebral perfusion imaging with the dual-tracer method may be advantageous in studying the effects of various drugs onregional cerebral perfusion, and in physiological tests

such as activation studies. Such investigations are currently under way in our laboratory.

ACKNOWLEDGMENTS

We express our thanks to Dr. T. Nukada (National Osaka SouthHospital, Osaka, Japan) and Dr. M. Imaizumi (National OsakaHospital)for helpfuldiscussions;to Mr. Y. Kusumi,Mr. H. Omori,Mr. Y. Nakamura and 1. Matsumoto for technical assistance; to MissM. Wada and Mrs. Y. Sato for secretarial assistance.

REFERENCES

I . MARSHALL J: The management of occlusion and stenosis ofthe internal carotid artery. Neurology(Mineap) I6:1087—1093,1966

2. CARTERAB: Cerebralinfarction,Oxford,Pergamon,I964,pp. 66-83

3. KRAYENBUHL HA, YASARGIL MG: Cerebral Angiography,London, Butterworths, 1968, pp. 165-184

4. TAVERASJM, WooD EH: Diagnosticneuroradiology,Baltimore, Williams & Willkins, 1976, pp. 857—911

5. GRIEPRJ,WISEG, MARTYR: Detectionofcarotid arteryobstruction by intravenous radionuclide angiography. Radiology97:311-316,1970

6. MISHKIN ES, DYKEN ML: Increased early radionuclideactivity in the nasopharyngeal area in patients with internalcarotid artery obstruction: “Hotnose.―Radiology 96:77-80,I970

7. MULLERHR:Thediagnosisof internalcarotidarteryocclusionby directional Doppler sonographyof the ophthalmicartery. Neurology(Mineap) 22:816-823, 1972

8. MAROON JC, CAMPBELL RL, DYKEN ML: Internal carotidartery occlusion diagnosed by Doppler ultrasound. Stroke1:122—127,1970

9. ZWIEBELWi, CRUMMYAB:SourcesoferrorinDopplerdiagnosis of carotid occlusive disease. Am J Roenigenol137:1—12,1981

10. KENNADY JC, SWANSON L, TAPLIN GV: Assessment ofcerebral microcirculation(basic and clinical studies). J NuclMed 8:267, 1967. (abst)

II. VERHAS M, SCHOUTENS A, DEMOL 0, et al: Use of99mTc..Iabeled albumin microsphere in cerebral vasculardisease.JNuclMed 17:170—174,1976

12. ETANIH, KIMURAK, IWATAY, etal:Internalcarotidocclusion: Assessment, by Tc-99m-tagged microspheres, ofbypass from superficial temporal to middle cerebral artery.JNucl Med 22:856-860, 1981

13. MEDURI M, BLANDINO G, LONGO M, et al: Ischemia in theterritory of the middle cerebral artery: Morphology of ischemic foci in the perfusional hemispheric scintigraphy. ActaNeurol(Napoli)35:173—180,1980

14. BRIZ-KANAFANI 5, GARCIA-MONTEMAYERE: Perfusionbrain scans and the anatomic lesions encountered: A correIation. Am J Roentgenol Radium Ther Nucl Med 109:681-691,1970

15. HAGAN PL, KREJCAREK GE, TAYLOR A, et al: A rapidmethod for the labelling of albumin microspheres with In-I I3

828 THE JOURNAL OF NUCLEAR MEDICINE

PRELIMINARY NOTES

and In- I I I : Concise communication. J Nucl Med 19:1055—1058,1978

16. MURPHY ES, CERVANTES CR, MAASS RE: Radioalbuminmacroaggregates brain scanning. A histopathologic investigation. Am J Roentgenol Radium Ther NuclMed 102:88-92,1968

17. BURDINEJA, SONNEMAKERRE, RYDERLA, et al: Per

fusion studies with technetium-99m human albumin microspheres(HAM). Radiology95:101-107,1970

18. LITrENBERG RL: Anaphylactoid reaction to human albuminmicrospheres. J Nucl Med I6:236—237,1975

19. GRAMES GM, JANSEN C, GANDER MP, et al: Safety of thedirect coronary injection of radiolabeled particles. I Nucl Med15:2—6,1974

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