Iomazenil Research Articles

False Lateralization of Mesial Temporal Lobe Epilepsy by Noninvasive Neurophysiological Examinations-Case Report-

Mesial temporal lobe epilepsy (mTLE) is the most common form of symptomatic localization-related epilepsy and is surgically remediable. Lateralization of the seizure onset is particularly important to determine from a surgical perspective. A 39-year-old woman with intractable mTLE first exhibited seizure at the age of 3 years. She experienced epigastric sensation and placed her right hand on her abdomen before falling backward. Although interictal scalp electroencephalography (EEG), sphenoidal scalp ictal EEG, and magnetoencephalography showed right temporal side focus, computed tomography and magnetic resonance imaging showed atrophy of the left cerebral hemisphere. Single photon emission computed tomography with technetium-99m ethyl cysteinate dimmer and I-123 iomazenil showed obscure focus on the left side. As a discrepancy existed between the results of neurophysiological examinations and imaging, we performed subdural electrode implantation on the bilateral temporal lobe. Although a bemegride-induced seizure arose from the right side during the subdural recording, the onset of 5 habitual seizures was observed in the left hippocampus. On the basis of these results, the seizure was diagnosed as left mTLE, and left anterior temporal lobectomy and amygdalohippocampectomy were performed. The patient has been free from the seizures for more than 1.5 years of follow up. Bilateral subdural electrode measurement of habitual seizures is indispensable for clarifying the actual focus when a discrepancy exists between neuroimaging and noninvasive neurophysiological examinations.

Evaluation of the use of a standard input function for compartment analysis of [123I]iomazenil data: Factors influencing the quantitative results

Adoption of standard input function (SIF) has been proposed for kinetic analysis of receptor binding potential (BP), instead of invasive frequent arterial samplings. The purpose of this study was to assess the SIF method in quantitative analysis of [123I]iomazenil (IMZ), a central benzodiazepine antagonist, for SPECT. SPECT studies were performed on 10 patients with cerebrovascular disease or Alzheimer disease. Intermittent dynamic SPECT scans were performed from 0 to 201 min after IMZ-injection. BPs calculated from SIFs obtained from normal volunteers (BPs) were compared with those of individual arterial samplings (BPo). Good correlations were shown between BP(o)s and BP(s)s in the 9 subjects, but maximum BP(s)s were four times larger than the corresponding BP(o)s in one case. There were no abnormal laboratory data in this patient, but the relative arterial input count in the late period was higher than the SIF. Simulation studies with modified input functions revealed that height in the late period can produce significant errors in estimated BPs. These results suggested that the simplified method with one-point arterial sampling and SIF can not be applied clinically. One additional arterial sampling in the late period may be useful.

Correct localization of epileptogenic focus with 1-123 iomazenil cerebral benzodiazepine receptor imaging: a case report of temporal lobe epilepsy with discordant ictal cerebral blood flow SPECT

A 26-year-old female with intractable epileptic seizures was studied with I-123 iomazenil cerebral benzodiazepine receptor, I-123 IMP inter-ictal and Tc-99m ECD ictal cerebral blood flow SPECT. The ictal cerebral blood flow SPECT indicated the location of the seizures to be in the left temporal lobe, where increased regional cerebral blood flow was noted in marked contrast to the inter-ictal SPECT. Ictal electroencephalograms (EEGs) recorded with scalp and sphenoidal electrodes also suggested the left temporal lobe as the location of the seizures. On I-123 iomazenil SPECT, however, decreased benzodiazepine receptor density was demonstrated in the right temporal lobe. MRI showed mild atrophy and abnormal signal intensity in the right temporal lobe. Ictal EEGs recorded with intracranial electrodes revealed that abnormal electrical activity of the brain always emerged from the right temporal lobe and then propagated to the contralateral side. Based on the findings of intracranial EEGs, partial resection of the right anterior temporal lobe including hippocampus was performed. After the surgery, no seizure occurred. Pathological examination of the surgical specimens revealed hippocampal sclerosis. This case suggested that cerebral benzodiazepine receptor imaging with I-123 iomazenil can be helpful for correct localization of epileptogenic foci.

Quantitative evaluation of central-type benzodiazepine receptors with [125I] Iomazenil in experimental epileptogenesisI. The rat kainate model of temporal lobe epilepsy

This study aimed at quantitatively evaluating hippocampal central-type benzodiazepine receptors (BZRs) in the kainate model of temporal lobe epilepsy (TLE) by in vitro autoradiography (ARG) using [125I] Iomazenil (IMZ) specific ligand for central-type BZRs. Kainate (1 μg/0.5 μl) was injected into the left amygdala to induce limbic status epilepticus. One, three, or six months after injection, in vitro ARG with [125I] IMZ and cell counts were performed in the hippocampal CA1–4 regions and dentate gyrus ipsilateral to the kainate injection site, and were compared with the vehicle-injected control group. In all kainate-treated rats, clear pyramidal neuron loss was observed in left hippocampal areas CA1–4. Compared with the control group, progressive reduction of [125I] IMZ binding was also observed. This resulted in a marked binding decrease paralleling pyramidal neuron loss in hippocampal areas CA1 (down to 83% of control), CA2 (76%), CA3 (75%), and CA4 (90%) at 6 months after kainate administration. Conversely, [125I] IMZ binding significantly increased in the dentate gyrus (up to 106% of control) at 1 month, but returned to nearly normal at 3–6 months. These results suggest that central-type BZR neuroimaging is useful in detecting hippocampal sclerosis in the mesial TLE, though central BZR alterations differ depending on hippocampal subfields and post-seizure time-courses.

Quantitative evaluation of central-type benzodiazepine receptors with [ 125I] Iomazenil in experimental epileptogenesis : I. The rat kainate model of temporal lobe epilepsy

This study aimed at quantitatively evaluating hippocampal central-type benzodiazepine receptors (BZRs) in the kainate model of temporal lobe epilepsy (TLE) by in vitro autoradiography (ARG) using [(125)I] Iomazenil (IMZ) specific ligand for central-type BZRs. Kainate (1 microg/0.5 microl) was injected into the left amygdala to induce limbic status epilepticus. One, three, or six months after injection, in vitro ARG with [(125)I] IMZ and cell counts were performed in the hippocampal CA1-4 regions and dentate gyrus ipsilateral to the kainate injection site, and were compared with the vehicle-injected control group. In all kainate-treated rats, clear pyramidal neuron loss was observed in left hippocampal areas CA1-4. Compared with the control group, progressive reduction of [(125)I] IMZ binding was also observed. This resulted in a marked binding decrease paralleling pyramidal neuron loss in hippocampal areas CA1 (down to 83% of control), CA2 (76%), CA3 (75%), and CA4 (90%) at 6 months after kainate administration. Conversely, [(125)I] IMZ binding significantly increased in the dentate gyrus (up to 106% of control) at 1 month, but returned to nearly normal at 3-6 months. These results suggest that central-type BZR neuroimaging is useful in detecting hippocampal sclerosis in the mesial TLE, though central BZR alterations differ depending on hippocampal subfields and post-seizure time-courses.

Quantitative evaluation of central-type benzodiazepine receptors with [ 125I]Iomazenil in experimental epileptogenesis: II. The rat cortical dysplasia model

[(123)I]Iomazenil (IMZ) is a specific ligand for central-type benzodiazepine receptors (BZRs) and is available for single photon emission computed tomography (SPECT) to detect epileptogenic foci. We have recently demonstrated time-dependent alterations of [(125)I]IMZ binding in the rat kainate model of temporal lobe epilepsy. Quantitative evaluation of central-type benzodiazepine receptors with [(125)I]Iomazenil in experimental epileptogenesis. I. The rat kainate model of temporal lobe epilepsy. In the present study, we investigated regional changes in central-type BZRs in the cortical dysplasia (CD) model of epilepsy in rats. Pregnant rats were irradiated at day 17 of gestation with 1.2 Gy to produce CD in their pups, and in vitro autoradiography with [(125)I]IMZ was performed at 8 weeks after birth. Intact rats at the same age were used as controls. [(125)I]IMZ binding was significantly decreased in various cortical regions of the in utero irradiated rats, including the bilateral frontal cortex (down to 92-93% of control), cingulate cortex (91-92%), hippocampal areas CA1 (95%), CA2 (94-95%) and CA4 (95-96%), and caudate/putamen (90-94%). In addition, amygdala-kindling was significantly facilitated in the CD model, especially during the late phase of kindling, suggesting seizure susceptibility of this model. These results may replicate the clinical usefulness of central-type BZRs neuroimaging for detection of human epileptogenic CD and indicate dysfunction of GABA-A/BZR-mediated inhibition responsible for the seizure susceptibility.

Is central benzodiazepine receptor imaging useful for the identification of epileptogenic foci in localization-related epilepsies?

In the presurgical evaluation of patients with partial epilepsies, the most extensively studied functional neuro-imaging modality to define the origin of seizure onset is fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET). Generally, this technique reveals a widespread zone of interictal glucose hypometabolism in the region of the epileptogenic focus. However, the technique may miss the epileptogenic region and FDG PET abnormalities may extend beyond the seizure onset zone. Consequently, for the precise identification of epileptogenic regions more specific imaging probes than FDG are warranted. This review considers the clinical utility of iomazenil (IMZ) SPET and flumazenil (FMZ) PET for the precise localization of epileptogenic foci in partial epilepsy syndromes.

Atrophy of the corpus callosum associated with a decrease in cortical benzodiazepine receptor in large cerebral arterial occlusive diseases

OBJECTIVESIt remains controversial whether selective neuronal ischaemic change develops in patients with occlusion of the large cerebral arteries. Previous studies have shown atrophy of the corpus callosum with reduced cortical...

Prediction of improvement of cerebral perfusion with I-123 iomazenil SPECT.

We report a case of 61-year old man who was suffering from cerebrovascular disease with right hemiparesis and received I-123 iomazenil (IMZ) SPECT prior to carotid endoarterectomy. Severe stenosis of the right internal carotid artery and occlusion of the left middle cerebral artery (MCA) were revealed by cerebral angiography, and a hypoperfused area in left MCA territory and crossed cerebellar diaschisis (CCD) on I-123 IMP SPECT was demonstrated. In contrast, IMZ SPECT showed symmetric normal distribution. After the carotid endoarterectomy, the hypoperfused area in left MCA territory on IMP SPECT and hemiparesis had improved. It is thought that IMZ SPECT can be a useful tool for the prediction of improvement of cerebral perfusion and the clinical outcome.

A Quantitative Study of Central Benzodiazepine Receptors in Surgically Resected Specimens with Temporal Lobe Epilepsy Using [125I]iomazenil Autoradiography

Purpose: We measured the density of central‐type benzodiazepine receptors (BZRs) in the surgically resected tissues from patients with temporal lobe epilepsy (TLE) by means of [125I]iomazenil (IMZ) autoradiography, and investigated the correlations between the BZDK density and neuronal cell density in the hippocampus. Methods: Resected tissues from 49 patients with TLE were studied after obtaining informed consent. The mean age at the onset of seizures was 9.4 years. and it was 25.7 years at surgery; the mean time between seizure onset and the operation was 16.3 years. In all patients, medically intractable complex partial seizures had occurred more than once per month before surgery. Anterior temporal lobectomy was conducted in 40 patients and selective amygdalohippocampectomy in nine patients. One group of 37 patients had mesial TLE (MTLE), and the other group or 12 patients had non‐MTLE. Of the 12 patients, three patients had a dysembryoplastic neuroepithelial tumor, three patients had an angioma, and three patients had a nonpathologic disease. Sixteen mi‐crometer‐thick cryostat sections were prepared from surgical specimens frozen immediately after resection. Those sections were incubated at 37°C for 1 h in a potassium phosphate buffer containing 150 mM NaCl and0.2 nM [125I]IMZ. Nonspecific binding was determined by coincubation with 1 μM diazepam (DZP). Autoradiographs were made by placing the radiolabeled slides on Hyperfilm‐3H. The densities of BZDR were calculated by using TVIP‐4100II and Image Command 4198 as TV image processors with [125I]microscale for the standard scale. The mean BZDR densities were calculated from several regions of interest (ROIs) in the identified lesions. The density of neurons in the hippocampal region also was quantified by using the Dam method. Results: In the non‐MTLE group, the laminated structures of the hippocampus had high accumulations of BZDR, especially in the molecular and granule cell layers of the dentate gym (mDG) and the molecular. radial, and pyramidal layers of the comuammonis (CA). In the MTLE group, decreased accumulation of BZDR binding corresponding to the severity of neuronal loss, especially in the radial and pyramidal layers of the CA, were observed. The decreased densities of the BZDR paralleled the loss of neurons in the hippocampal regions. In the MTLE group, the mean BZDR densities (fmol/mg tissue) were CAI, 4.25 ± 3.23; CA3, 8.44 ± 4.24; CA4, 11.64 ± 8.29; CM, 15.44 ± 5.77; and mDG, 52.89 ± 28.00. In the non‐MTLE group, these densities were CA1, 80.68 ± 29.33; CA4, 40.94 ± 4.24; CA3. 35.69 ± 6.76; CA2, 28.97 ± 6.11; and DGM, 87.5 ± 32.29. Significant differences between the MTLE and non‐MTLE BZDR densities were found in all regions of CA (p < 0.001) and in mDG (p < 0.001j. In the MTLE group, we investigated the correlations of the mean BZDR densities between each area of the hippocampus and the lateral temporal cortex. A positive correlation for the BZDR density was found between the mDG and the lateral cortex (p = 0.01; r= 0.744). Conclusions: The BZDR densities of the hippocampus in patients with ILE decreased in proportion to the severity of the neuronal loss. In the MTLE group, the BZDR density in the DGM was highly correlated with that of the temporal cortex. The positive correlation of the BZDR density between the mDG and the temporal lobe cortex suggests that hippocampal sclerosis or the epileptogenic foci affected the lateral cortex in patients with TLE. These results support the theory that functional imaging of the BZR is useful for diagnosing MTLE.

Quantitative Estimation of I-123-Iomazenil Receptor Binding in Temporal Lobe Epilepsies Using Two SPECT Acquisitions – Comparison with the Regional Cerebral Blood Flow and a Compartment Model

To compare published fractional rate constants of I-123-Iomazenil (IMZ) and C-11-Flumazenil (three-compartment/four-parameter model) with a I-123-Iomazenil receptor index calculated from two SPECT acquisitions and to compare the receptor index of the epileptogenic area with the contralateral side in patients with unilateral temporal lobe epilepsies. 28 patients were studied. 13/28 patients had a drug-resistant unilateral temporal lobe epilepsy with a successful focus localisation performed by an extensive video/EEG monitoring. 15 other patients with clinically suspected focal epilepsy and a normal MRI and IMZ SPECT scanning were used as controls. SPECT scanning was performed in all patients 15 and 100 min after intravenous injection of 111 MBq IMZ and 10 min after application of 740 MBq Tc-99m-HMPAO. Quantification of the regional uptake was performed using ROI-technique and the specific and non-specific binding of IMZ was calculated. The receptor index was calculated by the difference of the specific binding from 15 to 100 min p.i. divided by the time interval. The receptor index showed a linear correlation with recently published fractional rate constants k3 (r = 0.69 and 0.67; p = 0.15) and a moderate correlation with the k4 constant (-0.53 and -0.43; p = 0.28) by the means of C-11-Flumazenil PET and I-123-Iomazenil SPECT studies, respectively. However, statistical significance was not reached due to the few data points available from the published reports. Furthermore, the IMZ receptor index was lower in the epileptogenic area of patients with unilateral temporal lobe epilepsies compared with their contralateral side (p = 0.02; Wilcoxon-test). The IMZ receptor index showed a weak correlation with the regional cerebral blood flow independent of the evaluated region (r < 0.4; p < 0.05). The IMZ receptor index indicated to be a simple routine approach to estimate the fractional rate constant k3 (r = 0.67). The lower value of the receptor index within the epileptogenic area might be due to a lower receptor density. However in further studies, IMZ might be a helpful tool to find out subtle changes of the receptor affinity due to its approximately 30-fold higher ligand-receptor affinity compared to C-11-Flumazenil.

I-123 iomazenil SPECT in patients with mental disorders.

The purpose of this study is visual evaluation of the distribution of I-123 iomazenil in the brains of patients with various types of mental disorder and to examine whether chronic administration of a clinical dose of benzodiazepine (BZ) affects the binding of I-123 iomazenil to BZ receptors (BZR). The subjects were 10 patients with mental disorders (3 males and 7 females) with a mean age of 26.8 yrs (range 19-39 yrs). Four of 10 patients were administered BZ for over 3 months and the other six were free of BZ for over one month. The SPECT images were obtained at 5-25 min (early) and 170-190 min (delayed), after the bolus i.v. injection of 167 MBq of I-123 iomazenil, with a triple-head gamma camera. The images were visually evaluated and the washout ratios of each region were calculated. In visual analysis, abnormalities were recognized in 5 patients on the delaye SPECT. The abnormalities were recognized more frequently in the superior frontal lobe. The washout ratio was higher in the BZ (+) patient group than in the BZ (-) patient group. I-123 iomazenil is useful, because the SPECT image with I-123 iomazenil reflects the distribution of BZR on the brain and provides the different information from that obtained with perfusion SPECT, X-ray CT or MRI. The rapid washout of I-123 iomazenil from the brains of BZ (+) patients suggests that chronic administration of a clinical dose of BZ affects the binding of I-123 iomazenil to BZR.

Reduced cortical distribution volume of iodine-123 iomazenil in Alzheimer's disease as a measure of loss of synapses

Iodine-123 labelled iomazenil (IMZ) is a specific tracer for the GABAA receptor, the dominant inhibitory synapse of the brain. The cerebral distribution volume (Vd) of IMZ may be taken as a quantitative measure of these synapses in Alzheimer's disease (AD), where synaptic loss tends indiscriminately to affect all cortical neurons, albeit more so in some areas than in others. In this pilot study we measured Vd in six patients with probable AD and in five age-matched controls using a brain-dedicated single-photon emission tomography scanner allowing all cortical levels to be sampled simultaneously. Reduced values were found in all regions except in the occipital (visual) cortex. In particular, temporal and parietal cortex Vd was significantly (P<0.02) reduced: temporal Vd averaged 69 ml/ml in normals and 51 ml/ml in AD, and parietal Vd averaged 71 ml/ml in normals and 48 ml/ml in AD. These results accord well with emission tomographic studies of blood flow or labelled glucose. This supports the idea that while only measuring a subpopulation of synapses, the IMZ method reflects synaptic loss and hence functional loss in AD. The method constitutes an in vivo version of synaptic quantitation that in histopathological studies has been shown to correlate closely with the mental deterioration in AD.