Functional brain imaging with I123-amphetamine. First experience in the Netherlands C o l l a b o r a t i v e s t u d y II23-IMP w o r k i n g g r o u p : J.F. de B r m n e , E . A . van R o y e n , F. van W e e r e n , F . A . v . d . W e e l , S. R e i f f e r s , B . W . J . V e r b e e t e n jr, H. K r e n s , A. H i j d r a , and M. L i m b u r g Introduction Summary Brain scintigraphy has declined considerably after the introduction of computed tomography. The scintigraphic images cannot compete with the high resolution images of anatomic brain structures provided by CT scans. In ischemic brain disease both CT and Tc99m pertechnetate brain scintigraphy do not visualize infarcted tissue in the first days after its onset since both the contrast medium used for CT and Tc99m pertechnetate do not pass the intact blood brain barrier. Nuclear medicine, as an essentially functional technique is able to provide information on regional cerebral blood flow (rCBF). In the past rCBF has been investigated with Xe133, which only records CBF in superficial cortical tissue, and in more recent years with Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT). The latter may find much more clinical application than the P E T technique which is mainly confined to a few research centres. The SPECT technique employs widely available rotating gamma cameras and conventional radionuclides, instead of positron emitting nuclides which require cyclotron facilities on site. Tomographic imaging of rCBF with SPECT requires highly lipophilic radiopharmaceuticals which pass the intact blood brain barrier. Lipophilicity of a Single Photon Emission Computed Tomography (SPECT) has been used in the last five years as a method for cerebral bloodflow imaging, especially in cerebral infarction. In this study the first experiences in the Netherlands are presented. In 57.6% of our patients lesions, defined by SPECT were larger than those found by CT. This was not only seen in patients with cerebral infarction but also in hematoma. In 33.3% the size of the lesions were comparable. In 10 out of 14 patients with a solitary lesion in one hemisphere a decreased perfusion was seen in the contralateral cerebellar hemisfere. This phenomenon is called crossed cerebellar diaschisis. One patient with probably Alzheimer disease, showing a specific flowpattern, is discussed. Key words: SPECT, CT, cerebral infarction pharmacon and its clearance by the brain as a consequence is represented by a high octanol/ water partition coefficient. A high octanol/ water partition coefficient results in an almost 100% clearance of the agent after a single circulatory brain passage, which is obligatory in the measurement of rCBF. Thereafter a stable level of brain retention should occur for at least about 30 min, in order to obtain SPECT images. After i.v. injection, the ideal radiopharmacon Academic Medical Center, Amsterdam; Hospital 'De Stadsmaten ', Enschede; Hospital 'De Weezenlanden', Zwolle; Hospital 'Het Nieuwe Spittaal', Warnsfeld; Cvgne, Technische Hogeschool, Eindhoven. Address for correspondence and reprint requests: E.A. van Royen, Department of Nuclear Medicine, Academisch Medisch Centrum, Meibergdreef 9, 1105 A Z Amsterdam. Accepted 9.9.86 Clin Neurol Neurosurg 1986. Vol. 88-4 253 Fig. la Fig. lb Fig. 1: Transversal CT (a) and SPECT (b) slice. CT shows cortical atrophy and slightlyenlarged ventricles. The asymmetry of the occipital horns is also seen on the SPECT image. In Table t the different gamma camera systems, computers and acquisition parameters are listed. All departments use a 360 degree acquisition and reconstruction employing filtered backprojection. for rCBF imaging must distribute instantaneously to the various brain structures and stick there like microspheres injected into the carotid arteries, resulting in a 'frozen image' of rCBF at the time of injection. Winchell developed N-isopropyl- 123IP-Iodoamphetamine (123I-IMP) 1,2, which is highly lipophilic and has a high extraction rate in the first pass. I123-IMP shows also a constant brain activity between 20 and 60 min. after intravenous injection 3. It has been stated therefore that I123-IMP images of the brain represent rCBF. Fig. la shows an example of a transversal slice with a CT image on the same level (Fig. lb). In recent years several reports have appeared on I123-IMP SPECT studies of the brain in various disorders 4-~2. The present study reports on the first experiences with I123-IMP/SPECT brain imaging in the Netherlands. Materials and Methods In order to achieve greater uniformity between studies, the four participating institutes agreed upon a more or less standardized procedure. 254 Patient studies A total of 48 studies were performed, 24 patients were male and 24 female. 73% of the patients were between 50 and 80 years old. The various disorders of the patients are listed in Table 2. The largest group (36) consisted of patients with ischaemic cercbrovascular disease. After a 30 rain. rest with a low background level of noise and light, 3-5 mCi I123-IMP (Cygne, T H Eindhoven) was injected ~ -'~ antecubital vein, while the patient was lying in supine position. After 15-30 minutes, acquisition of the S P E C T images were started. In about one fifth of the studies, patients were given 10 mgr diazepam per os before the I123-IMP injection (Het Nieuwe Spittaal, Warnsveld). Every patient underwent also a CT study. In 44% both examinations were made within a period not exceeding 5 days. In 4 cases SPECT and CT were performed on the same day, while in 23 cases first the CT and in 21 cases first the S P E C T study was done. In 12.5% (6 cases) the period between both studies exceeded 20 days, the Table 1. Type of gamma camera's, computers and acquisition parameters used by the participating institutes. METHODS AND MATERIALS ZWOLLE ENSCHEDE AMSTERDAM WARNSVELD gamma camera Gen.Electr. 400 T Gen.Electr. 400 T Technicare Omega 500 Technicare Omega 500 collimator low energy parallelhole low energy 30 slanthole 300 KeV parallelhole 300 KeV parallelhole computer Digital PD 11/34 Informatec 1502 Technicare MCS 560+AP Technicare MCS 560+AP 30 37 27 30 slice thickness (pixel, mm) (2, 12.6) (1, 6.3) (2, 11.2) (2, 11.6) filter type modified Shepp-Logan Parzen Butterworth 0.35/4 Butterworth 0.35/4 total imaging time (min.) m a x i m u m was 40 days. In 33.3% of the cases the p e r i o d b e t w e e n the o n s e t of the disease a n d the first study was less t h a n o n e week. I n 25% this p e r i o d was b e t w e e n o n e a n d six weeks, while in 41.7% this p e r i o d was m o r e t h a n six weeks. C T a n d S P E C T images were reviewed indep e n d e n t l y by e x p e r i e n c e d r e p r e s e n t a t i v e s of the radiology a n d n u c l e a r m e d i c i n e d e p a r t m e n t s of the p a r t i c i p a t i n g institutes. N u m b e r a n d size of the h y p o d e n s e a n d in case of h e m o r r h a g i c area's the h y p e r d e n s e areas o n the C T were c o m p a r e d with n u m b e r a n d size of the areas with d i m i n i s h e d activity on S P E C T . In S P E C T studies of ischemic b r a i n disease special a t t e n t ion was given to a r e d u c e d u p t a k e in the contralateral cerebellar hemisphere, a phenomenon called crossed cerebellar di~?h_isis ( C C D ) . This was only p e r f o r m e d in patients with lesions c o n f i n e d to one h e m i s p h e r e . This p h e n o m e n o n has b e e n described both in the S P E C T literature s as in the P E T literature 13 a n d is due to a d i m i n i s h e d c e r e b e l l a r bloodflow c o n t r a l a t e r a l to the in- Table 2. List of diagnosis of the examined patients. Diagnosis male female total Cerebrovascular disease - infarction M.C.A. infarction posterior watershed area multiple infarctions brain stem infarction - TIA/RIND basilar insufficiency (19) 6 (17) 8 (36) 14 3 5 2 3 - 7 1 1 3 12 3 3 1 Hematoma (without trauma) 1 Trauma 2 Epilepsy 1 Dementia 0 Migraine Accompagnee 0 Metastasis 1 Unknown 0 1 2 2 1 0 1 2 2 3 2 1 1 1 Total 24 48 - - - - 24 Table 3. Comparison of the hypo- and hyperdense areas on CT and the areas with diminished activity on SPECT. farcted h e m i s p h e r e . R e s u l t s F o u r t y - s e v e n C T studies showed 64 h y p o d e n s e or h y p e r d e n s e areas, while 58 areas with d i m i n i s h e d activity were recognized on the S P E C T studies. T h i r t y - t h r e e of these areas were c o m p a r a b l e r e g a r d i n g the localization (Table 3). T h e p a t i e n t with the m u l t i p l e metastasis was hypo/hyperdense areas on CT 64 areas with diminished activity on SPECT 58 CT area < SPECT area 19 (57.6%) CT area = SPECT area 11 (33.3%) CT area > SPECT area 3 (9.1%) one patient was excluded (multiple metastasis) 255 T a b l e 4. C o m p a r i s o n Vascular area o f S P E C T a n d C T a r e a ' s s u b d i v i d e d in v a s c u l a r r e g i o n s . hypo/hyperdense area (CT) area diminish. act. ( S P E C T ) CT area < SPECT area CT area = SPECT area CT area > SPECT area ant.cerebral artery 3 1 - 1 - middle cerebr. artery - superficial - deep - combined 16 22 8 17 4 9 4 3 4 4 1 3 - post.cerebral artery 2 3 1 1 - ant.watershed area 4 2 1 6 post.watershed area (bilateral, no of patients) 8 22 (1) (4) brain stem 1 . excluded (of the 5 rather small metastases on enhanced CT, only one with a large area of o e d e m a was recognized on S P E C T as a cold spot). In 57.6% of the cases the S P E C T showed a larger area of diminished uptake, in 33.3% both areas had an equal size, while in 9.1% the CT area was larger, when c o m p a r e d to the S P E C T area. The hypodense areas on CT and the areas with diminished activity on S P E C T were classified according to the known vascular areas, the anterior ( A C A ) , the middle (MCA) and the posterior cerebral artery (PCA). The M C A area was subdivided in a superficial, deep and combined superficial and deep area. The watershed areas and the brain stem were classified seperately. The results are given in Table 4. Most striking was the lower sensitivity of the S P E C T study in the deep areas. On the other hand S P E C T revealed more lesions in the posterior watershed area. In general, if lesions corresponded, S P E C T lesions were larger than those found by CT. The occurrence of crossed cerebellar diaschisis (CCD) related to the diagnosis is 256 . . - 2 - 1 1 . shown in Table 5. Fourteen cases with single lesions could be studied. In 10 patients a CCD was found, in 3 patients the activity in both cerebellar hemispheres was equal and in 1 case the ipsilateral cerebellar hemisphere showed a decrease in activity c o m p a r e d to the contralateral one. Cerebrovascular disease Thirty-six patients were suffering from cerebrovascular disease. Fourteen patients had a M C A infarction. In 7 cases the S P E C T area was larger when c o m p a r e d to the CT area, while in 2 cases the S P E C T and CT area were equal in size. In none of the cases the CT area appeared larger. In two cases CT was positive while S P E C T showed no abnormalities, while in one case S P E C T showed an area with diminished activity, with a normal CT. In two cases both S P E C T and CT were abnormal, but the areas were not comparable. Of the 14 patients with M C A infarction in 9 cases the cerebellum was included in the study. Seven S P E C T studies showed a positive C C D , one cerebellum was normal and in one case the ipsilateral cerebellum showed a decrease in activity (Fig. 2a + b). Table 5. The occurrence of crossed cerebellar diaschisis related to the diagnosis. Diagnosis CCD+ CCD- MCA infarct 7 1 post.watershed infarct 1 1 hematoma, parietal 2 - hematoma, frontal - 1 TOTAL l0 3 diminished activity in ipsilateral cerebellar hemisphere 1 total 14 The patients with multiple lesions were excluded Fig. 2: Case 2; streaklike hypodense area on CT (a) in the parietal region, probably in the external capsula or claustrum (arrow). SPECT shows a very large area of decreased activity on the same side (b). CCD is clearly shown (arrowhead). vity in t h e right M C A a r e a . O n e o f the o t h e r p a t i e n t s s h o w e d a d e c r e a s e d activity in b o t h p o s t e r i o r w a t e r s h e d regions. In the t h i r d p a t i e n t both SPECT and CT were normal. Two patients with TIA's w e r e i n v e s t i g a t e d . O n e p a t i e n t h a d a l a c u n a r i n f a r c t i o n on C T in t h e b a s a l ganglia o f the left side, while S P E C T s h o w e d a d e c r e a s e in activity in t h e p o s t e r i o r w a t e r s h e d a r e a on t h e right. T h e o t h e r p a t i e n t h a d a d e c r e a s e d activity in the P C A r e g i o n with a n o r m a l CT. O n e p a tient s u f f e r e d f r o m a R I N D o f the right M C A , S P E C T was positive while C T r e v e a l e d no abnormalities. Basilar insufficiency was s e e n in one p a t i e n t . C T was n o r m a l while S P E C T s h o w e d an a r e a of d e c r e a s e d activity in the left M C A region. C C D was p r e s e n t . W e s t u d i e d two p a t i e n t s with a spontaneous intracerebral h e m a t o m a of which o n e was c a u s e d by a r u p t u r e d saccular a n e u r y s m a . In b o t h cases the S P E C T a r e a with d i m i n i s h e d activity, l o c a l i z e d in t h e left p a r i e t a l r e g i o n , was Fig. 2a Fig. 2b Three patients had a posterior watershed area infarction. In all 3 cases the a r e a on S P E C T was larger. In two cases the c e r e b e l l u m was i n c l u d e d in the s t u d y of which o n e h a d a p o s i t i v e C C D . N o p a t i e n t s w e r e s t u d i e d with a solitary infarction o f t h e A C A , P C A o r in the a n t e r i o r w a t e r s h e d region. T w e l v e p a t i e n t s w e r e s t u d i e d with multiple infarctions. C T s h o w e d 36 h y p o d e n s e areas, while 19 cases with d i m i n i s h e d activity w e r e seen with S P E C T . O f the 13 c o m p a r a b l e a r e a s 5 w e r e l a r g e r on S P E C T , 5 w e r e e q u a l in size a n d in 3 cases the C T lesion was larger. Brain stem i n f a r c t i o n was s e e n in 3 p a t i e n t s . O n l y o n e was p o s i t i v e o n CT. I n this p a t i e n t t h e S P E C T s t u d y s h o w e d an a r e a o f d e c r e a s e d acti- 257 Fig. 3a Fig. 3: Case 1; hypodense area in the right parietal region (a), SPECT (b) shows a much larger area of reduced uptake on the right side (arrows). CCD is present (arrowhead). larger when c o m p a r e d to the h e m a t o m a on CT. A crossed cerebellar diaschisis was present in both cases. Two trauma patients were examined. One patient had a left sided contusion on CT in the deep parietal region, S P E C T showed a decrease in cortical activity uptake on the same side. The other trauma patient revealed a frontal h e m a t o m a with an equal sized area of reduced activity on SPECT. In this case no CCD was present. Epilepsy. One patient was examined who underwent a craniotomy in 1962 for an arteriovenous malformation and presented recently with seizures. On CT hypodense areas were seen in the right sided M C A and P C A regions. These were equal in size when compared to the areas seen on the S P E C T study. Two other patients with seizures were examined. One had a normal CT and an area with decreased activity in the right M C A region on the S P E C T study. The third patient showed no abnormal findings on CT or SPECT. All patients were examined at an interictal phase. Two patients with dementia were studied. A 57-year-old female presented with progressing forgetfulness. A diagnosis of presenile dementia was made (Alzheimer disease). CT was normal. S P E C T showed a bilateral parieto-occipital decrease in activity. The other patient was an 80-year-old female suffering from multi infarction dementia. On CT cortical atrophy and enlarged ventricles were seen. S P E C T showed a 258 Fig. 3b small rim of activity accumulation in the cortical areas. One patient with migraine accompagnee was examined. Both CT and S P E C T were normal. The patient was painfree during SPECT. In one patient with doubtful neurological symptoms no diagnosis could be established. No focal abnormalities were found with CT or SPECT. Case studies Case 1. A 66-year-old female presented with an acute leftsided hemiparesis. CT was performed 13 days after onset and showed a small hypodense area on the right side deep parietal, with asymmetry of the ventricles due to compression. S P E C T was p e r f o r m e d the next day and revealed a large cortical area with diminished activity on the right side (Fig. 3a, b). The left cerebellar hemisphere showed diminished activity when compared to the right hemisphere (positive CCD). Case 2. A 79-year-old male underwent both a CT and a S P E C T study 3 months after the onset of a rightsided hemiparesis and aphasia. The CT Fig. 4. Case 3; CT shows some cortical tissue loss (a), while SPECT reveals bilateral areas of reduced uptake in the parietooccipital regions suggesting Alzheimer's disease (b). study showed loss of cortical tissue and enlarged ventricles (Fig. 2a, b). Hypodense areas were found surrounding the anterior horn of the lateral ventricles possibly representing leucoencephalomalacia. Another hypodense area was seen lateral of the left basal ganglia. The SPECT study revealed a large cortical lesion on the left side with diminished activity, which included most of the region. The CCD phenomenon was also positive in this patient. Case 3. A 57-year-old female was admitted to the hospital suffering from a slowly progressive loss of memory. She could not manage daily housekeeping and did irresponsable purchases. Neurological examination revealed no abnormality. A diagnosis of probable Alzheimer disease was made. C T study showed some loss of cortical tissue without focal disorders (Fig 4a, b). On the SPECT study bilateral reduced activity was seen in the parietal region which did not correspond with any abnormality on the CT scan. Discussion I231-IMP is taken up by the brain tissue almost completely during the first pass, whereafter it is retained for a period of 20-60 min. Therefore its distribution is highly flow dependent and when no further uptake or redistribution occurs, the injection represents the flow pattern at the time of injection. This resembles a 'frozen image' of cerebral bloodflow (CBF) obtained after the intracarotid injection of microspheres. Probably this hypothesis is only valid for I123-IMP uptake in normal brain tissue, since uptake and retention maybe influenced byamine receptors, pH changes and metabolism6, Lee et al 6 were unable to show focal hyperemia, 'luxurious perfusion', in any of their stroke patients. This may be due to alteration of the infarcted tissue, so that uptake and retention are diminished in spite of increased flow. Also in our study we did not observe luxurious perfusion. Another argument that retention of I123-IPM does not depend fully on CBF is posed by the decreased uptake of I123-IMP in brain tumours 4,8,17. In 57.6% of our patients lesions defined by SPECT were larger than those found by CT. This phenomenon was also reported by others 3,6,9,1~ and may be due to the 'penumbra' effect ~~ In acute stroke CT shows often little or no abnormalities in the first days, while the perfusion defects, shown by I123-IMP can be demonstrated immediately after the onset. The SPECT study proved to have a substan259 tially lower sensitivity for small and deeply localized lesions. While CT demonstrated 22 deep M C A lesions only 4 were found by SPECT, probably because of the low spatial resolution of the present rotating g a m m a cameras. Crossed cerebellar diaschisis (CCD) proved to be a frequent finding. In 71.4% (10 out of 14) of our patients with solitary lesions C C D was present. This p h e n o m e n o n was not confined to stroke patients but also observed in h e m a t o m a and tumors. It is probably related to a reduced neuronal activity in the cerebellum hemisphere caused by a deprivation of input of impulses from the contralateral infarcted cerebral hemisphere resulting in a reduced metabolism and blood flow L3. Diaschisis has also been described in the contralateral hemisphere and the ipsilateral thalamus to a cortical infarction 13. The localization of epileptic foci registered by E E G , may be very difficult especially in case of deep lesions. CT is only helpful if morphotogic changes are present. Localization of the focus may be of interest when stereotactic or surgical intervention is considered. If 123I-IMP is injected during a seizure, a S P E C T study may be p e r f o r m e d afterwards. Then the focus may still be present as an area of increased activity caused by the increased blood flow during the seizure 6,9,18,19,2~ If the injection is administered during the postictal or interictal state, the focus may present as a cold area due to a decreased blood flow of the focus. We studied two patients in an interictal Case, with both normal CT's. One case showed an area of decreased activity on SPECT, which might represent the focus. The other patient showed no abnormalities on SPECT. The differential diagnosis of dementia may be difficult, especially in the early phase. In nonvascular forms, employing S P E C T a symmetrical decrease in cerebral blood flow in the tempero-parietal-occipital areas has been described 2~ while in multi-infarction dementia S P E C T may reveal discrete multiple asymmetrical gray matter defects. Decreased activity in the parieto-occipital areas was observed in case 3 suffering from Alzheimer disease. More experience has to be gathered before conclusions can be drawn as to the value of S P E C T in the differential diagnosis of dementia. 260 In summary single photon emission computed t o m o g r a p h y offers a complementary method when functional disorders, particularly concerning CBF, are present. In acute stroke S P E C T may be the method of choice to monitor ischemia in intervention studies aimed to diminish the loss of neurons in the ' p e n u m b r a ' area. When stereotactic or surgical intervention in patients with epilepsy is considered, the focus can be detected with S P E C T when 123I-IMP is injected during the epileptic fit. Moreover S P E C T may add considerably to the differential diagnosis of dementia. References Development of 1-123-1abeled amines for brain studies, localisation of 1-i23 Iodophenylalkylamines in rat brain. J Nucl Med 1980; 21:940-6. WINCHELL HS, BALDWIN RM, LIN TH. W1NCHELL HS~ HORST WD, BRAUN L, OLDENDORF WH, HATTNER R and PONKER H. 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