Faculty Bibliography

OBJECTIVE:Using interictal alpha-[11C]methyl-l-tryptophan ([11C]AMT) PET scan, the authors have undertaken a quantitative analysis of all tubers visible on MRI or 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) PET, to determine the relationship between [11C]AMT uptake and epileptic activity on EEG. BACKGROUND:Tuberous sclerosis complex (TSC) is an autosomal dominant disorder, often associated with cortical tubers and intractable epilepsy. The authors have shown previously that [11C]AMT PET scans show high tracer uptake in some epileptogenic tubers and low uptake in the remaining tubers. METHODS:Eighteen children, age 7 months to 16 years, were studied. Patients underwent video-EEG monitoring, PET scans of [11C]AMT and [18F]FDG, and T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI. [11C]AMT uptake values were measured in 258 cortical tubers delineated with coregistered MRI or [18F]FDG scans. Uptake ratios were calculated between the [11C]AMT uptake in tubers and those for normal cortex (tuber/normal cortex). Using the region of epileptiform activity, the authors performed receiver operator characteristics (ROC) analysis and determined the optimal uptake ratio for detecting presumed epileptogenic tubers. RESULTS:Tuber uptake ratios ranged from 0.6 to 2.0. Tuber uptake ratios in the epileptic lobes were higher than those in the nonepileptic lobes (p < 0.0001). All 15 patients with focal seizure activity showed one or more lesions with uptake ratio above 0.98 in the epileptic lobe. ROC analysis showed that a tuber uptake ratio of 0.98 resulted in a specificity of 0.91. CONCLUSIONS:Cortical tubers with [11C]AMT uptake greater than or equal to normal cortex are significantly related to epileptiform activity in that lobe. Together, interictal [11C]AMT PET and FLAIR MRI improve the detection of potentially epileptogenic tubers in patients with TSC being evaluated for epilepsy surgery.

The purpose of this study was to examine the relation between glucose metabolism and glutamate concentration in the human brain, in both the normal and diseased state. Regional values of glucose metabolism measured with 2-deoxy-2[F-18]fluoro-D-glucose positron emission tomography (FDG PET) studies and single-voxel proton magnetic resonance spectroscopy (1H MRS) measurements of the glutamate/ glutamine/gamma-aminobutyric acid (Glx) tissue concentration were determined in multiple brain regions in 11 patients (5 girls and 6 boys, mean age 7.5 years) with medically intractable partial epilepsy. FDG PET and 1H MRS studies were performed in the interictal state in seven patients and in the ictal/periictal state in four patients. Regions of interest were identified in epileptic cortex (determined by intracranial and/or scalp electroencephalography) and in contralateral normal brain regions. Lower glucose metabolism and lower Glx concentrations were found in the epileptic focus than in the contralateral normal cortex in all seven patients examined in the interictal state, whereas higher glucose metabolism and higher Glx concentrations were observed in the epileptic focus in the four patients who had ictal/periictal studies. Significant correlations were found between the values of cerebral glucose utilization and Glx concentration in epileptic brain region, in nonepileptic brain regions, and in epileptic and nonepileptic regions combined. These results demonstrate a significant relation between glucose metabolism and glutamate/glutamine concentration in normal and epileptic cerebral cortex. This relation is maintained in both the interictal and ictal states.

OBJECTIVE:To compare abnormalities determined in 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and [11C]flumazenil (FMZ) PET images with intracranial EEG data in patients with extratemporal lobe epilepsy. BACKGROUND:Although PET studies with FDG and FMZ are being used clinically to localize epileptogenic regions in patients with refractory epilepsy, the electrophysiologic significance of the identified PET abnormalities remains poorly understood. METHODS:We studied 10 patients, mostly children (4 boys, 6 girls, aged 2 to 19 years; mean age, 11 years), who underwent FDG and FMZ PET scans, intracranial EEG monitoring, and cortical resection for intractable epilepsy. EEG electrode positions relative to the brain surface were determined from MRI image volumes. Cortical areas of abnormal glucose metabolism or FMZ binding were determined objectively based on asymmetry measures derived from homotopic cortical areas at three asymmetry thresholds. PET data were then coregistered with the MRI and overlaid on the MRI surface. A receiver operating characteristics (ROC) analysis was performed to determine the specificity and sensitivity of PET-defined abnormalities against the gold standard of intracranial EEG data. RESULTS:FMZ PET detected at least part of the seizure onset zone in all subjects, whereas FDG PET failed to detect the seizure onset region in two of 10 patients. The area under the ROC curves was higher for FMZ than FDG PET for both seizure onset (p = 0.01) and frequent interictal spiking (p = 0.04). Both FMZ and FDG PET showed poor performance for detection of rapid seizure spread (area under the ROC curve not significantly different from 0.5). CONCLUSIONS:[11C]flumazenil (FMZ) PET is significantly more sensitive than 2-deoxy-2-[18F]fluoro-D-glucose (FDG) PET for the detection of cortical regions of seizure onset and frequent spiking in patients with extratemporal lobe epilepsy, whereas both FDG and FMZ PET show low sensitivity in the detection of cortical areas of rapid seizure spread. The application of PET, in particular FMZ PET, in guiding subdural electrode placement in refractory extratemporal lobe epilepsy will enhance coverage of the epileptogenic zone.

Positron emission tomography (PET) is a relatively noninvasive neuroimaging method by means of which a large variety of human brain functions can be assessed. Localized neurochemical abnormalities detected by PET were found in patients with partial epilepsy and suggested the use of this modality for localizing epileptogenic regions of the brain. The clinical usefulness of PET is determined by its sensitivity and specificity for identifying epileptogenic areas as defined by ictal surface and intracranial EEG recordings. The findings obtained from comparative EEG and glucose PET data are reviewed with special emphasis on patients undergoing presurgical evaluation because of medically intractable temporal and extratemporal lobe epilepsy. The utility of glucose PET studies for identifying regions of seizure onset is presented, and the limited specificity of glucose metabolic abnormalities for the detection of various EEG patterns in clinical epilepsy is discussed. The authors review the available intracranial EEG and PET comparisons using [11C]flumazenil (FMZ) PET, a tracer for the assessment of tau-amino-butyric acid/benzodiazepine receptor function. They also summarize their experience with [11C]flumazenil PET in identifying cortical regions that show various ictal and interictal cortical EEG abnormalities in patients with extratemporal seizure origin. Finally, the authors demonstrate that further development of new PET tracers, such as alpha-[11C]methyl-L-tryptophan, is feasible and clinically useful and may increase the number of patients in whom PET studies can replace invasive EEG monitoring.

Our results and those of others demonstrate that the development of new PET probes with increasing sensitivity and specificity for epileptogenic brain regions is feasible. Further development of novel tracers guided by knowledge of the biochemical characteristics of epileptogenic cortex from basic studies is the logical next step in the application of neuroimaging to localize epileptogenic cortex. Furthermore, computational advances allowing coregistration of biochemical images with high-resolution MRI anatomic images, as well as electrophysiologic data sets, not only has practical value in guiding surgical resection of epileptogenic neocortex, but this approach contributes to further understanding of the biochemical mechanisms involved in the pathophysiology of neocortical epilepsy.

OBJECTIVES/OBJECTIVE:To analyze interictal patterns of thalamic nuclei glucose metabolism and benzodiazepine receptor binding in patients with medically intractable temporal lobe epilepsy (TLE) using high-resolution 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and [11C]flumazenil (FMZ) PET. BACKGROUND:Structural and glucose metabolic abnormalities of the thalamus are considered important in the pathophysiology of TLE. The differential involvement of various thalamic nuclei in humans is not known. METHODS:Twelve patients with TLE underwent volumetric MRI, FDG and FMZ PET, and prolonged video-EEG monitoring. Normalized values and asymmetries of glucose metabolism and FMZ binding were obtained in three thalamic regions (dorsomedial nucleus [DMN], pulvinar, and lateral thalamus [LAT]) defined on MRI and copied to coregistered, partial-volume-corrected FDG and FMZ PET images. Hippocampal and amygdaloid FMZ binding asymmetries and thalamic volumes also were measured. RESULTS:The DMN showed significantly lower glucose metabolism and FMZ binding on the side of the epileptic focus. The LAT showed bilateral hypermetabolism and increased FMZ binding. There was a significant correlation between the FMZ binding asymmetries of the DMN and amygdala. The PET abnormalities were associated with a significant volume loss of the thalamus ipsilateral to the seizure focus. CONCLUSIONS:Decreased [11C]flumazenil (FMZ) binding and glucose metabolism of the dorsomedial nucleus (DMN) are common and have strong lateralization value for the seizure focus in human temporal lobe epilepsy. Decreased benzodiazepine receptor binding can be due to neuronal loss, as suggested by volume loss, but also may indicate impaired gamma-aminobutyric acid (GABA)ergic transmission in the DMN, which has strong reciprocal connections with other parts of the limbic system. Increased glucose metabolism and FMZ binding in the lateral thalamus could represent an upregulation of GABA-mediated inhibitory circuits.

UNLABELLED:[11C]flumazenil (FMZ) imaged with PET allows the computation of parametric images of both tracer influx (K1) and volume of distribution (VD). The VD images, which allow visualization of a quantitative measure of benzodiazepine receptor binding, are reported to have high sensitivity and specificity for the delineation of epileptic foci. However, the clinical feasibility of this method is compromised by the necessity of arterial blood sampling. We therefore compared the performance of parametric VD images against simple FMZ activity images for the detection of neocortical epileptic foci. METHODS:FMZ PET data from 7 children with extratemporal lobe epilepsy (mean age [+/- SD] 9.8+/-4.4 y) and 6 healthy adult volunteers (mean age [+/- SD] 40+/-8 y) were analyzed using a semiautomated analysis algorithm. FMZ activity images and parametric VD images were analyzed for asymmetry with cutoff thresholds of 8%, 10% and 12%. RESULTS:The time frame between 10 and 20 min after injection represented overall the best agreement between FMZ activity and VD images independent of the threshold. The normal asymmetry in VD images was determined as 6.4%+/-1.4% and was significantly higher in the FMZ activity images (7.6%+/-1.4%, P = 0.001). Increasing the cutoff threshold resulted in a significant decrease in the area defined as abnormal in both the VD and the FMZ activity images. Abnormalities defined in FMZ activity images identified additional brain regions as abnormal at the 8% threshold, but there was good agreement with VD images at the 10% asymmetry threshold. In those regions where abnormalities in VD and FMZ activity images were not matched, the asymmetry indices obtained from K1 images were significantly higher than those derived from the VD images (P = 0.01). CONCLUSION/CONCLUSIONS:Differences between VD and activity images above the 8% threshold are mainly due to K1. Abnormalities defined in FMZ activity images using a threshold of 10% agree well with those obtained from parametric VD images, indicating that activity images obtained from the time frame of 10-20 min are essentially equivalent to VD images with regard to detection of regions of abnormality for seizure focus localization.

OBJECTIVE:To measure brain serotonin synthesis with PET using the tracer alpha-[11C]methyl-L-tryptophan in migraine patients. BACKGROUND:Although the cause of migraine remains poorly understood, there is considerable evidence to support a role of the neurotransmitter serotonin in the pathophysiology of migraine. METHODS:We studied 11 women (aged 33+/-7.7 years) with a diagnosis of migraine according to International Headache Society criteria and 8 healthy women (aged 29+/-9.2 years). Five patients were studied before and after chronic treatment with propranolol or nadolol. RESULTS:Serotonin synthesis capacity (K-complex) values in migraine patients were higher than those measured in controls throughout the brain (p = 0.016); mean K-complex for whole brain was 0.0077 + 0.0020 mL/g/min in patients with migraine and 0.0054+/-0.0003 mL/g/min in controls. The regional pattern did not differ between the two groups. However, the K-complex for whole brain in the subgroup of migraine patients with aura (n = 3) did not differ from that of the control group (p = 0.32). In the five patients studied twice (before and after treatment), we found a trend of increased whole-brain K-complex after drug treatment (p = 0.06). CONCLUSIONS:Our findings indicating increased brain serotonin synthesis capacity in migraine patients are consistent with previous reports of systemic alteration of serotonin metabolism in patients without aura. Our results also suggest that the mechanism of action of beta-adrenergic antagonists for migraine prophylaxis may involve regulation of serotonin synthesis.