[11C]Flumazenil Positron Emission Tomography Visualizes Frontal Epileptogenic Regions

Summary: Presently available noninvasive methods correctly localize epileptogenic regions in only ε50% of patients with frontal lobe epilepsy (FLE). Earlier studies have shown that temporal lobe epileptogenic regions may be identified readily by positron emission tomography (PET) measurements of regional benzodiazepine (BZD) receptor binding. We tested the specific applicability of this method in patients with FLE. Six patients with frontal partial seizures and 7 healthy men were investigated with PET and the BZD receptor ligand [¹¹C]flumazenil. All patients had magnetic resonance (MR) brain scans. The independent assessment of seizure–onset region was based on seizure semiology, intra– and extracranial EEG and, in 4 cases, also on [¹⁸F]fluorodeoxyglucose (FDG) PET. The epileptic focus/seizure-generating region was correctly identified by [¹¹C]flumazenil PET in all patients. This region was characterized by a significant reduction in BZD receptor density. The area with reduced BZD receptor density was better delimited than the corresponding hypometabolic region, which was observed in 50% of patients investigated with [¹⁸F]FDG–PET. MRI was normal in 5 patients. Visualization of BZD receptors with [¹¹C]flumazenil PET appears to be a promising approach for noninvasive identification of frontal lobe epileptogenic regions.     

Benzodiazepine-GABAA Receptors in Idiopathic Generalized Epilepsy Measured with [11C]Flumazenil and Positron Emission Tomography

Summary The neurochemical basis of absence seizures and the mechanism of their suppression by valproate (VPA) are uncertain. We used positron emission tomography (PET) to determine whether an abnormality of [¹¹C]flumazenil binding to benzodiazepine (BZD)-GABA_A receptors exists in patients with childhood and juvenile absence epilepsy and to examine the effects of VPA on [¹¹C] flumazenil binding. The regional cerebral volume of distribution ( V _d) of [¹¹C]flumazenil in patients not treated with VPA was not different from that in normal controls; V _d was lower in patients treated with VPA, and the number of receptors available for binding was significantly reduced in such patients as compared with normal controls. There was no evidence of a primary abnormality of the BZD-GABA, receptor in childhood and juvenile absence epilepsy (CAE/JAE), but the data suggest that treatment with VPA is associated with a reduction in [¹¹C]flumazenil binding that may be relevant to its mode of action in CAE/JAE.     

Striatal kinetics of [11C]-(+)-nomifensine and 6-[18F]fluoro-L-dopa in Parkinson''s disease measured with positron emission tomography

The kinetics in brain of the dopamine reuptake blocking agent [11C]-(+)-nomifensine and the L-dopa analogue 6-[18F]fluoro-L-dopa were compared in 3 patients with idiopathic Parkinson's disease and age-matched healthy volunteers using positron emission tomography. Regional uptake was analyzed and quantified according to a 3-compartment model. Retention of both tracers in striatal regions of the parkinsonian patients were reduced compared with the healthy volunteers mainly in the putamen, while the caudate nucleus was only mildly affected. The reductions were considerably less than the decrease previously reported postmortem for striatal dopamine content in the basal ganglia of patients with Parkinson's disease. A fairly constant ratio between 6-[18F]fluoro-L-dopa utilization and [11C]-(+)-nomifensine binding in the caudate nucleus and the putamen were found in both groups unrelated to the size of the estimated parameters. This indicates that a limiting factor for the utilization of exogenous levodopa in Parkinson's disease may be a reduced transport capacity for the amino acid into the dopaminergic terminals.     

False Lateralization of Temporal Lobe Epilepsy with FDG Positron Emission Tomography

Summary: We report 2 patients in whom visual interpretation of interictal positron emission tomography (PET) with [¹⁸F]fluorodeoxyglucose (FDG) suggested false lateralization of an epileptic focus. PET scans were interpreted as showing diffuse left temporal lobe hypometabolism in 1 patient and lateral temporal hypometabolism in the other. However, seizures began in the right mesial temporal lobe in both patients, and both responded favorably to right temporal lobectomy. In 1 patient, the intra-cranial EEG showed continuous asymptomatic subclinical seizure activity emanating from the right amygdala. These limbic discharges probably caused unrecognized right temporal lobe hypermetabolism. In the other case, quantitative analysis of metabolic rates showed conflicting mesial and lateral metabolic indexes. Frequent mesial interictal discharges might have increased lateral temporal metabolism. We conclude that asymptomatic epileptiform activity may alter temporal lobe metabolism and that quantitative PET analysis helps clarify contradictory visual PET interpretations.     

[11ClFlumazenil PET in Patients with Epilepsy with Dual Pathology

PURPOSE: Coexistence of hippocampal sclerosis and a potentially epileptogenic cortical lesion is referred to as dual pathology and can be responsible for poor surgical outcome in patients with medically intractable partial epilepsy. [11C]Flumazenil (FMZ) positron emission tomography (PET) is a sensitive method for visualizing epileptogenic foci. In this study of 12 patients with dual pathology, we addressed the sensitivity of FMZ PET to detect hippocampal abnormalities and compared magnetic resonance imaging (MRI) with visual as well as quantitative FMZ PET findings. METHODS: All patients underwent volumetric MRI, prolonged video-EEG monitoring, and glucose metabolism PET before the FMZ PET. MRI-coregistered partial volume-corrected PET images were used to measure FMZ-binding asymmetries by using asymmetry indices (AIs) in the whole hippocampus and in three (anterior, middle, and posterior) hippocampal subregions. Cortical sites of decreased FMZ binding also were evaluated by using AIs for regions with MRI-verified cortical lesions as well as for non-lesional areas with visually detected asymmetry. RESULTS: Abnormally decreased FMZ binding could be detected by quantitative analysis in the atrophic hippocampus of all 12 patients, including three patients with discordant or inconclusive EEG findings. Decreased FMZ binding was restricted to only one subregion of the hippocampus in three patients. Areas of decreased cortical FMZ binding were obvious visually in all patients. Decreased FMZ binding was detected visually in nonlesional cortical areas in four patients. The AIs for these nonlesional regions with visual asymmetry were significantly lower than those for regions showing MRI lesions (paired t test, p = 0.0075). CONCLUSIONS: Visual as well as quantitative analyses of FMZ-binding asymmetry are sensitive methods to detect decreased benzodiazepine-receptor binding in the hippocampus and neocortex of patients with dual pathology. MRI-defined hippocampal atrophy is always associated with decreased FMZ binding, although the latter may be localized to only one sub-region within the hippocampus. FMZ PET abnormalities can occur in areas with normal appearance on MRI, but FMZ-binding asymmetry of these regions is lower when compared with that of lesional areas. FMZ PET can be especially helpful when MRI and EEG findings of patients with intractable epilepsy are discordant.     

NMDA-Receptor Activity Visualized with (S)-[N-Methyl-11C]Ketamine and Positron Emission Tomography in Patients with Medial Temporal Lobe Epilepsy

Summary: Purpose: To determine whether neurochemical activation of the N-methyl-D-aspartate (NMDA) receptor-gated ion channel shows quantitative changes, measured as binding of ¹¹C-labeled (S)-[N-methyl]ketamine, in patients with medial temporal lobe epilepsy (MTLE). Methods: Eight patients with MTLE who were evaluated regarding epilepsy surgery underwent positron emission tomography (PET) with (S)-[N-methyl-¹¹C]ketamine. The presurgical investigations included magnetic resonance imaging (MR1), PET with ¹⁸F-fluoro-deoxyglucose (¹⁸FDG), and seizure monitoring by using video-EEG. The uptake of (S)-[N-methyl-¹¹C]ketamine in the temporal lobe of ictal onset was compared with the contralateral side and correlated to changes in regional glucose metabolism measured by PET with ¹⁸FDG. Results: (S)-[N-methyl-¹¹C]ketamine rapidly reached the brain, and high radioactivities were measured in the striatum, thalamic nuclei, and cortical regions. Overall the brain uptake and regional binding potentials of (S)-[N-methyl-¹¹C]ketamine were similar to measurements observed previously in healthy controls. However, 20 min after administration, when blood flow influence was negligible, a side-to-side comparison revealed a 9–34% reduction of tracer radioactivity in the temporal lobes of ictal onset. At earlier times, the differences in binding potentials were less pronounced, 9–21%. The magnitude and distribution of the reduction were similar to the metabolic pattern seen on PET scans with ¹⁸FDG. Conclusions: Radioactivity uptake of intravenously administered (S)-[N-methy]-¹¹C]ketamine was reduced in temporal lobes of ictal in patients with TLE. This may reflect reduced NMDA-receptor density, reduced perfusion, focal atrophy, or other factors.     

Functional Neuroimaging with Positron Emission Tomography

Summary: Epilepsy research using positron emission tomography (PET) has provided considerable new information about ictal and interictal dysfunctions in human epilepsy. Neuroreceptor mapping with PET ligands has revealed altered central benzodiazepine receptor and opiate receptor densities in partial epilepsies interictally, and regional increases in endogenous opioid peptide concentrations during absence seizures. Imaging of perfusion and glucose metabolism during cognitive processing has shown interictal abnormalities of regional activation in partial and generalized epilepsies. The diagnostically robust patterns of interictal glucose hypometabolism are not adequately explained by macrostructural and microstructural alterations in temporal lobe epilepsy. Current investigations of the pathophysiology of interictal hypometabolism must address ultrastructural and neurochemical factors. Clinical PET in pre-surgical evaluation of medically refractory epilepsies remains an active area of research, but remarkably little antiepileptic drug research has exploited PET techniques.     

Diagnosis of Temporal Lobe Epilepsy by Positron Emission Tomography

Abstract. Temporal lobe epilepsy was studied by the ¹¹C-glucose method of positron emission tomography. The temporal lobe at the level 25 mm above the orbitomeatal line showed the amygdala, hippocampus and hippocampal gyrus medially, and the T1, T2 and T3 neocortices laterally. The focus locations in these structures were divided into mesial, lateral and combined groups on the PECT images. This classification showed a close correlation between the clinical symptoms and the anatomical focus sites.     

Estimation of regional cerebral utilization of [11C]-L-3, 4-dihydroxy-phenylalanine (DOPA) in the primate by positron emission tomography

The intracerebral kinetics of [11C]-labelled L-3,4-dihydroxyphenylalanine, L-DOPA, was investigated in rhesus monkeys by positron emission tomography (PET). Through the labelling of the L-DOPA molecule in different positions and observation of a series of pharmacological challenges it was possible to establish that the kinetic conversion of the radiotracer in the striatum represents the process of decarboxylation to [11C]-labelled dopamine. The rate constant for this process can be estimated using a two-compartment model. The use of [11C]-L-DOPA and PET will thus provide a possibility for in vivo studies of blood-brain barrier transport of the amino acid as well as for the estimation of the ability for brain tissue to decarboxylate the tracer by the action of aromatic L-amino acid decarboxylase.     

Cerebral uptake and utilization of therapeutic [β-11C]-L-DOPA in Parkinson''s disease measured by positron emission tomography. Relations to motor response

Cerebral uptake and utilization of levodopa was measured in eight patients with idiopathic Parkinson's disease (PD) by [beta-11C]-L-DOPA and positron emission tomography (PET). By adding pharmacological doses of unlabelled levodopa to the radioactive solution it was possible to evaluate the clinical effect simultaneously with the cerebral kinetics of the drug. Additionally, in two of the patients with advanced PD, investigations with the dopamine re-uptake blocker [11C]-(+)-nomifensine and PET were carried out to get a measure of the density of striatal dopaminergic nerve-terminals. The brain uptake of [beta-11C]-L-DOPA was inversely correlated to the sum of large neutral amino acids in plasma. In the eight PD patients studied with [beta-11C]-L-DOPA striatal k3, which reflects the ability for striatal tissue to decarboxylate the tracer by the action of aromatic L-amino acid decarboxylase (AADC), was decreased 35% compared to healthy subjects. It was demonstrated that, in the patients with advanced PD and motor fluctuations on oral L-DOPA medication, reversal of parkinsonian symptoms occurred at very low striatal tissue dopamine concentrations. In the two very advanced patients studied with [11C]-(+)-nomifensine the striatal binding of the tracer was 50% reduced.     

Central Benzodiazepine/γ-Aminobutyric AcidA Receptors in Idiopathic Generalized Epilepsy: An [11C]Flumazenil Positron Emission Tomography Study

Summary: Purpose: Previous [¹¹C]flumazenil (FMZ) positron emission tomography (PET) investigations in patients with idiopathic generalized epilepsy (IGE) have demonstrated nonsignificant global cortical decreases in central benzodiazepine γ-aminobutyric acid, (GABA_A) receptor (cBZR) binding or focal decreases in the thalamus and increases in the cerebellar nuclei with no changes in cerebral cortex. We previously reported lower [¹¹C]FMZ binding in cerebral cortex of IGE patients treated with valproate (VPA) than in cerebral cortex of controls. We now report high-resolution three-dimensional [¹¹C]FMZ PET studies in a larger number of subjects using an improved method to detect differences in cBZR between IGE patients and controls and a more powerful longitudinal design to determine the functional effect of VPA.
Methods: We compared parametric images of [¹¹C]FMZ volume of distribution (FMZVD) in 10 IGE patients before and after addition of VPA and in 20 normal subjects.
Results: Mean FMZVD was significantly higher in the cerebral cortex (11%, p = 0.009), thalamus (14%, p = 0.018), and cerebellum (15%, p = 0.027) of the 10 IGE patients as compared with that of 20 normal controls. Using statistical parametric mapping, no significant areas of focal abnormality of FMZVD were detected. Addition of VPA was not associated with a significant change in mean FMZVD in any brain area.
Conclusions: Our finding of increased FMZVD in IGE could reflect microdysgenesis or a state of cortical hyperexcitability. Our data suggest that short-term VPA therapy does not affect the number of available cBZR in patients with IGE.     

Ictal 99mTc-HMPAO Single Photon Emission Computed Tomography in Children with Temporal Lobe Epilepsy

Seventeen ictal ^99mTc-HMPAO single photon emission computed tomography (SPECT) studies were performed in 15 children with temporal lobe epilepsy (TLE) aged 7–14 years (mean 10.3 years). Ictal SPECT was informative in 16 of 17 (94%) studies in 14 of 15 (93%) children, showing unilateral temporal lobe hyperperfu sion. In all 16 informative ictal SPECT studies, lateral-ization was concordant with ictal EEC, magnetic resonance imaging (MRI), and pathology. In 4 children, ictat SPECT provided additional localizing information that was not apparent from concurrent ictal EEC recording. Blinded interpretation of ictal SPECT studies by two independent investigators showed correct lateralization of the epileptic focus in every child. Results of visual analysis of ictal SPECT images were corroborated by quantitative analysis. Although interictal SPECT studies showed a degree of temporal lobe hypoperfusion in all children, in 9 of 15 hypoperfusion was either minimal, bilateral, contralateral, or associated with extratemporal hypoperfusion. In children with TLE, ictal SPECT provides reliable lateralizing information to corroborate or supplement that obtained from surface EEG and MRI.     

Effect of Seizures on Cerebral Blood Flow Measured with 15–H2O and Positron Emission Tomography

Summary: To study quantitative alterations in regional cerebral blood flow (rCBF) accompanying seizures, and to assess the utility of ictal activation PET scanning as a noninvasive clinical tool for localization of epileptogenic foci, we used pentylenetetrazole (F'TZ) to induce seizures during ¹⁵O-water positron emission tomography (PET) CBF measurement in 15 patients with uncontrolled complex partial seizures (CPS) who had been referred for surgical evaluation. Continuous EEG monitoring was performed during the PET scans. After baseline scans were obtained, each patient was injected with 150–300 mg PTZ. Two patients had generalized tonic-clonic seizures (GTCs). CBF increases were asymmetrical. Two patients (in 1 the seizure occurred spontaneously, without PTZ injection) who had CPS had bitemporal 70–80% increases in CBF. Thalamic CBF increased during both CPS and GTCS. Five patients had an increase in focal EEG in-terictal abnormality, accompanied by focal flow decreases in 3. PTZ injection not accompanied by clinical seizures did not increase CBF. Partial seizures may be associated with bilateral increases in CBF, and subcortical gray regions are involved in ictal activation.     

Regional increases in [11 C]flumazenil binding after epilepsy surgery

Introduction – Animal experiments suggest that epileptic seizures alter the expression of mRNA for neuro-receptors. PET measurements with [¹¹ C]flumazenil show that patients with partial seizures have a reduced density of benzodiazepine (BZ) receptors in the epileptogenic regions (ER) and some of the target areas for seizure activity, the so called projection areas. Recent data suggest that the degree of BZ receptor reduction in ER is correlated to seizure frequency. We therefore hypothesized that seizure activity can alter the BZ receptor binding, and that some of these changes could normalize when the seizures disappeared. Methods – In 4 patients whose seizures were generated by mesial temporal lobe structures, BZ receptor density was measured with [¹¹ C]flumazenil PET before, and 1 year after the epilepsy surgery and cessation of seizures. By use of a computerized anatomical brain atlas the same regions were analyzed in both PET scans, and the results related to data from 7 healthy controls. Results – Presurgical PET scans showed reductions in BZ receptor density in the epileptogenic region and some of its primary projection areas. Other cortical regions had normal values. Postsurgically, the calculated BZ receptor density normalized (29±17% increase) in several of the affected projection areas, whereas the values in other cortical regions remained unaltered. Conclusion – Regional reductions in BZ receptor density may be dynamic and related to seizures. The present preliminary observations encourage further studies on seizure-related changes in regional receptor binding in humans.     

Effect of Valproate on Cerebral Metabolism and Blood Flow: An 18F-2-Deoxyglusose and 15O Water Positron Emission Tomography Study

Summary: We compared the effect of valproate (VPA) on cerebral metabolic rate for glucose (CMRGlc) and cerebral blood flow (CBF), measured with ¹⁸F-2–deoxyglucose (^I8FDG) and ¹⁵O water positron emission tomography (PET), in 10 normal volunteers. Mean VPA dose was 17.7 mg/kg, and mean VPA level was 82.1 mg/L (±16.5) for 4 weeks. VPA reduced global CMRGlc by 9.4% (9.60 2 0.76 vs. 8.59 ± 1.02 mg Glc/min/100 g, p < 0.05) and regionally in all anatomic areas (p < 0.05 for 11 of 26 areas). VPA diminished global CBF by 14.9% (56.55 ± 6.70 vs. 47.48 ± 4.42 ml/min/100 g, p < 0.002) and regionally in all anatomic areas (p < 0.05 for 12 of 26 areas). No significant correlation was noted between VPA level and either global CMRGlc or CBF. The effect of VPA on global CMRGlc is similar to that of carbamazepine (CBZ) and phenytoin but less than that of phenobarbital, Valium, or combination therapy with VPA and CBZ. VPA reduced regional CBF (rCBF) but not CMRGlc in the thalamus, an effect that may be associated with VPA's mechanism of action against generalized seizures.     

Changes in GABAA receptor properties in amygdala kindled animals: in vivo studies using [11C]flumazenil and positron emission tomography

Purpose: The purpose of the present investigation was to quantify alterations in GABA_A receptor density in vivo in rats subjected to amygdala kindling. Methods: The GABA_A receptor density was quantified by conducting a [¹¹C]flumazenil (FMZ) positron emission tomography (PET) study according to the full saturation method, in which each animal received a single injection of FMZ to fully saturate the GABA_A receptors. Subsequently, the concentration‐time curves of FMZ in blood [using high‐pressure liquid chromatography with UV detector (HPLC‐UV) or high‐performance liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS)] and brain (with PET‐scanning) were analyzed by population modeling using a pharmacokinetic model, containing expressions to describe the time course of FMZ in blood and brain. Results: The GABA_A receptor density (B_max) in kindled rats was decreased by 36% compared with controls. This is consistent with a reduction of 28% in electroencephalography (EEG) effect of midazolam in the same animal model, suggesting that a reduced number of GABA_A receptors underlies the decreased efficacy of midazolam. Furthermore, receptor affinity (K_D) was not changed, but the total volume of distribution in the brain (V_Br), is increased to 178% of control after kindling, which might indicate an alteration in the transport of FMZ across the blood–brain barrier. Conclusions: Both the GABA_A receptor density (B_max), and possibly also the blood–brain barrier transport of FMZ (V_Br) are altered after kindling. Furthermore, this study indicates the feasibility of conducting PET studies for quantifying moderate changes in GABA_A receptor density in a rat model of epilepsy in vivo.     

Novel Neuroimaging Findings in a Patient with Cerebral Whipple''s Disease: A Magnetic Resonance Imaging and Positron Emission Tomography Study

The authors report a 43-year-old patient with histopathologically proven cerebral Whipple's disease. Magnetic resonance imaging (MRI) revealed a multilayered left frontal lesion without mass effect, no perifocal brain edema, no contrast enhancement, and a thin shell of fluid signal that presented as an incomplete, open ring. An [11C]methionine positron emission tomography (PET) study showed low uptake below the threshold that is characteristic for brain tumors. In precise co-registration to the MR images, the PET data showed that increased uptake was mainly located in the direct adjacent part of the MRI lesion. The fluid signal on MRI corresponded to the extensive outflow of fluid from the lesion, which was observed during neurosurgical resection, and also to the neuropathological findings. The authors conclude that this cerebral manifestation of Whipple's disease made a unique and hitherto undescribed appearance on MRI; uptake pattern of PET amino acid tracer may help in the preoperative distinction of inflammatory from neoplastic lesions.