Intracranial EEG versus flumazenil and glucose PET in children with extratemporal lobe epilepsy

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.     

Relationship between EEG and positron emission tomography abnormalities in clinical epilepsy.

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.     

Positron emission tomography in presurgical localization of epileptic foci

The success of cortical resection for intractable epilepsy of neocortical origin is highly dependent on the accurate presurgical delineation of the regions responsible for generating seizures. In addition to EEG and structural imaging studies, functional neuroimaging such as positron emission tomography (PET) can assist lateralization and localization of epileptogenic cortical areas. In the presented studies, objectively delineated focal PET abnormalities have been analyzed in patients (mostly children) with intractable epilepsy, using two different tracers: 2-deoxy-2-[18F]fluoro-D-glucose (FDG), that measures regional brain glucose metabolism, and [11C]flumazenil (FMZ), that binds to GABAA receptors. The PET abnormalities were correlated with scalp and intracranial EEG findings, structural brain abnormalities, as well as surgical outcome data. In patients with extratemporal foci and no lesion on MRI, FMZ PET was more sensitive than FDG PET for identification of the seizure onset zone defined by intracranial EEG monitoring. In contrast, seizures commonly originated from the border of hypometabolic cortex detected by FDG PET suggesting that such areas are most likely epileptogenic, and should be addressed if subdural EEG is applied to delineate epileptic cortex. In patients with cortical lesions, perilesional cortex with decreased FMZ binding was significantly smaller than corresponding areas of glucose hypometabolism, and correlated well with spiking cortex. Extent of perilesional hypometabolism, on the other hand, showed a correlation with the life-time number of seizures suggesting a seizure-related progression of brain dysfunction. FMZ PET proved to be also very sensitive for detection of dual pathology (coexistence of an epileptogenic cortical lesion and hippocampal sclerosis). This has a major clinical importance since resection of both the cortical lesion and the atrophic hippocampus is required to achieve optimal surgical results. Finally, the author demonstrated that in patients with neocortical epilepsy, FDG PET abnormalities correctly regionalize the epileptogenic area, but their size is not related to the extent of epileptogenic tissue to be removed. In contrast, complete resection of cortex with decreased FMZ binding predicts good surgical outcome suggesting that application of FMZ PET can improve surgical results in selected patients with intractable epilepsy of neocortical origin.     

Electroclinical correlates of flumazenil and fluorodeoxyglucose PET abnormalities in lesional epilepsy

OBJECTIVE: To analyze the clinical utility of [11C]flumazenil (FMZ) PET to detect perilesional and remote cortical areas of abnormal benzodiazepine receptor binding in relation to MRI, 2-deoxy-2-[18F]fluoro-d-glucose (FDG) PET, and electrocorticographic (ECoG) findings as well as clinical characteristics of the epilepsy in epileptic patients with brain lesion. BACKGROUND: The success of resective surgery in patients with medically intractable epilepsy and brain lesion depends not only on removal of the lesion itself but also on the reliable presurgical delineation of the epileptic cortex that commonly extends beyond it. PET could provide a noninvasive identification of such epileptogenic areas. METHODS: Seventeen patients underwent high resolution MRI, FDG and FMZ PET, and presurgical EEG evaluation, including chronic intracranial ECoG monitoring or intraoperative ECoG. Regional cortical FDG/FMZ PET abnormalities were defined on partial volume-corrected PET images using an objective method based on a semiautomated definition of areas with abnormal asymmetry. Structural lesions were defined on coregistered MRI. The marked PET abnormalities visualized on three-dimensional cortical surface were compared with each other, to the extent of MRI-defined lesion, as well as to ECoG findings. RESULTS: The mean surface extent of FMZ PET abnormalities was significantly larger than the corresponding structural lesions, but it was significantly smaller than areas of glucose hypometabolism. The size of perilesional FDG PET abnormalities showed a correlation with the lifetime number of seizures (r = 0.93, p = 0.001). The extent of perilesional FMZ PET abnormalities was independent of the seizure number and showed an excellent correspondence with spiking cortex, the resection of which resulted in seizure-free outcome in all but one operated patient. Remote FMZ PET abnormalities (n = 6) were associated with early age at seizure onset (p = 0.048) and appeared in ipsilateral synaptically connected regions from the lesion area. CONCLUSIONS: Three-dimensional surface-rendered FMZ PET is able to delineate perilesional epileptic cortex, and it may be especially useful to localize such areas in patients with extensive perilesional glucose hypometabolism associated with a large number of seizures. Remote FMZ PET abnormalities in patients with early onset and long duration of epilepsy might represent secondary epileptogenesis, but this requires further study.     

Relationship of flumazenil and glucose PET abnormalities to neocortical epilepsy surgery outcome.

BACKGROUND: Cortical areas showing abnormal glucose metabolism and [(11)C]flumazenil (FMZ) binding are commonly seen on PET scans of patients with intractable partial epilepsy, but it is unclear whether these must be totally resected to achieve seizure control. OBJECTIVE: To analyze whether the extent of cortex showing 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) or FMZ PET abnormalities correlates with the outcome of resective epilepsy surgery. METHODS: Cortical FDG and FMZ PET abnormalities in 15 young patients (mean age, 12.2 +/- 7.0 years) with intractable partial epilepsy of neocortical origin were marked as regions with abnormal asymmetry using an objective semiautomated software package. These marked regions were then projected and measured on the brain surface reconstructed from the coregistered high-resolution MRI. Following cortical resection, the size of nonresected cortex with preoperative PET abnormalities was also measured (calculated separately for marked areas in the lobe of seizure onset as defined by long-term video EEG monitoring, and in remote cortical areas). Extent of preoperative PET abnormalities and postoperative nonresected cortex abnormalities on PET were correlated with outcome scores. RESULTS: Large preoperative FMZ PET abnormalities were associated with poor outcome (r = 0.57; p = 0.025). Larger areas of nonresected cortex with preoperative FMZ PET abnormalities in the lobe of seizure onset were also associated with worse outcome in the whole group (r = 0.66; p = 0.007) as well as in patients with extratemporal resection (r = 0.73; p = 0.007), and in those with no lesion on MRI (r = 0.60; p = 0.049). Patients with seizure-free outcome had significantly smaller nonresected cortex with preoperative FMZ PET abnormalities than those who continued to have seizures (p = 0.022). No significant correlations between nonresected FDG PET abnormalities and surgical outcome were found. CONCLUSIONS: Extensive cortical abnormalities on FMZ PET predict poor outcome in neocortical epilepsy surgery. Resection of FMZ abnormalities in the lobe of seizure onset is associated with excellent outcome even in the absence of a structural lesion. In contrast, although FDG PET abnormalities regionalized the epileptogenic area, their size was not related to the extent of epileptogenic tissue to be removed.     

Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex

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.     

Positron Emission Tomography with [11C]Deuterium-Deprenyl in Temporal Lobe Epilepsy

Summary: We performed positron emission tomography (PET) with [¹¹C]deuterium-deprenyl in 9 patients with temporal lobe epilepsy (TLE) undergoing evaluation for possible epilepsy surgery. Seven patients had unilateral and 2 had bilateral mesiotemporal epileptic foci based on the preoperative investigation including ictal EEG discharges and PET with 2-[¹⁸F]fluoro-2-deoxyglucose (FDG). Deprenyl is an irreversible inhibitor of mono-amine oxidase type B (MAO-B) with a very high affinity for the enzyme. In the brain, MAO-B is preferentially located in astrocytes, and a previous in vitro study showed increased binding of the ligand in sclerotic hippocampi. Dynamically acquired N-[methyl-¹¹C]-a, a-di-deutero-L-deprenyl distributions in PET images were analyzed graphically, and the focus regions were assessed visually on the PET images. In addition, the accumulation rate and distribution volume of the tracer relative to the cerebellar cortex were measured in standardized homologous temporal regions by semiquantitative methods. Uptake of [¹¹C]deuterium-deprenyl was significantly increased in the epileptogenic temporal lobes, both apparently and semiquantitatively. By calculating mean inter-lobar ratios, we identified the temporal lobe containing the epileptic focus in six unilateral cases. One case was ambiguous but was not falsely localized. The two bilateral cases were correctly identified as such. Our results suggest that PET with [¹¹C]deuterium-deprenyl might be a useful method for identification of epileptogenic temporal lobes.     

Functional neuroimaging in the preoperative evaluation of children with drug-resistant epilepsy

Functional neuroimaging Although the primary imaging modality in the management of epilepsy is magnetic resonance imaging MRI, functional neuroimaging with positron-emission tomography (PET) and single photon emission computed tomography (SPECT) often provides complementary information and, in a number of situations, provides unique information that cannot be obtained with MRI. The most commonly used PET tracers used for epilepsy evaluation are 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) and [¹¹C]flumazenil (FMZ). Recently, interictal PET with alpha-[¹¹C]methyl-l-tryptophan was found to be highly specific for the epileptic focus and can differentiate between epileptogenic and nonepileptogenic lesions in the same patient (e.g., in patients with tuberous sclerosis).Discussion In this review, we discuss clinical applications of these three PET tracers in drug-resistant temporal and extratemporal lobe epilepsy, selected epilepsy syndromes of childhood, lesional and nonlesional epilepsy, and the challenges of imaging secondary epileptic foci. A brief discussion of SPECT applications in epilepsy is also included. With further development of new tracers highly sensitive and specific for epileptogenic brain regions, the presurgical evaluation of refractory epilepsy will be greatly facilitated. Approximately 0.5 to 1.0% of the population suffer from epilepsy, of which 15–20% are intractable. Infants and children, whose seizures have a focal onset are refractory to anticonvulsants and are prolonged, tend to have the worst cognitive outcome [Meador KJ, Neurology 58 (Suppl 5):S21–S26, 2002]. Seizures themselves affect the developing brain and contribute to an adverse neurologic outcome (Holmes, Pediatric Neurology 33:1–110, 2005).Conclusion Therefore, in treating children with intractable epilepsy, it is important to consider seizure control and to give allowance for normal cognitive development.     

[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.     

Localizing value of alpha-methyl-L-tryptophan PET in intractable epilepsy of neocortical origin.

BACKGROUND: [(11)C] alpha-methyl-L-tryptophan (alpha-MTrp) has been developed as a tracer for the study of the synthesis of serotonin in the brain with PET. However, it has been shown that in pathologic conditions the tracer may reflect the activation of kynurenine metabolism. Increased levels of serotonin and quinolinic acid have been described in resected epileptogenic cortex, raising the possibility that alpha-MTrp can localize seizure foci in patients with intractable partial epilepsy. The authors assessed the uptake of alpha-MTrp in 18 patients (11 men, mean +/- SD age 27.1 +/- 10.1 years, range 13 to 54) with intractable partial epilepsy to correlate the PET findings with the epileptogenic area defined by electroclinical and neuroimaging data. METHOD: Seven patients with cortical dysplasia (CD) and 11 with partial epilepsy in which conventional MRI and fluorine-18-deoxyglucose ((18)FDG)-PET studies failed to detect any abnormality were studied. All underwent scalp EEG monitoring during the PET scan to exclude ictal events and estimate the interictal epileptic activity. RESULTS: In seven patients (39%; CD four and cryptogenic partial epilepsy three), PET showed focal increased uptake of alpha-MTrp corresponding to the epileptogenic area. alpha-MTrp uptake in the epileptic focus correlated with the frequency of interictal spikes (r = 0.7, p < 0.05). CONCLUSIONS: alpha-MTrp-PET may be of value in the localization of the epileptogenic area not only in patients with visible dysplastic lesions, but also in those with cryptogenic partial epilepsy.     

Glucose and [11C]flumazenil positron emission tomography abnormalities of thalamic nuclei in temporal lobe epilepsy

OBJECTIVES: 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.     

Clinical utility of 11C-flumazenil positron emission tomography in intractable temporal lobe epilepsy

BACKGROUND: 11C-flumazenil (FMZ) positron emission tomography (PET) is a new entrant into the armamentarium for pre-surgical evaluation of patients with intractable temporal lobe epilepsy (TLE). AIMS: To analyze the clinical utility of FMZ PET to detect lesional and remote cortical areas of abnormal benzodiazepine receptor binding in relation to magnetic resonance imaging (MRI), 2-Deoxy-2 [18F] fluoro-D-glucose, (18F FDG) PET, electrophysiological findings and semiology of epilepsy in patients with intractable TLE. MATERIALS AND METHODS: Patients underwent a high resolution MRI, prolonged Video-EEG monitoring before 18F FDG and 11C FMZ PET studies. Regional cortical FMZ PET abnormalities were defined on co-registered PET images using an objective method based on definition of areas of abnormal asymmetry (asymmetry index {AI}>10%). SETTINGS AND DESIGN: Prospective. STATISTICAL ANALYSIS: Student's "t" test. RESULTS: Twenty patients (Mean age: 35.2 years [20-51]; M:F=12:8) completed the study. Mean age at seizure onset was 10.3 years (birth-38 years); mean duration, 23.9 years (6-50 years). Concordance with the MRI lesion was seen in 10 patients (nine with hippocampal sclerosis and one with tuberous sclerosis). In the other 10, with either normal or ambiguous MRI findings, FMZ and FDG uptake were abnormal in all, concordant with the electrophysiological localization of the epileptic foci. Remote FMZ PET abnormalities (n=18) were associated with early age of seizure onset (P=0.005) and long duration of epilepsy (P=0.01). CONCLUSIONS: FMZ-binding asymmetry is a sensitive method to detect regions of epileptic foci in patients with intractable TLE.     

Interictal cerebral metabolism in partial epilepsies of neocortical origin

We performed interietal [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG PET) in 24 patients with partial epilepsy of neocortical origin. Two-thirds of patients had regions of hypometabolism. The zone of intracranially recorded electrographic ictal onset was always located in a region of hypometabolism, in those with hypometabolism. Hypometabolic regions in partial epilepsies of neocortical origin were usually associated with structural imaging abnormalities. Regional hypometabolism occasionally occurred without localizing ictal scalp EEG and cerebral magnetic resonance imaging findings, however. FDG PET may be useful in directing placement of intracranial electrodes for presurgical evaluation of refractory neocortical seizures.     

Disparity of perfusion and glucose metabolism of epileptogenic zones in temporal lobe epilepsy demonstrated by SPM/SPAM analysis on 15O water PET, [18F]FDG-PET, and [99mTc]-HMPAO SPECT

PURPOSE: To elucidate uncoupling of perfusion and metabolism and its significance in epilepsy, 15O water and 18F fluorodeoxyglucose (FDG) positron emission tomography (PET) and Tc-99m hexamethyl-propyleneamine-oxime (HMPAO) single-photon emission computed tomography (SPECT) were examined by SPM (statistical parametric mapping) and quantitation by using SPAM (statistical probabilistic anatomic map). METHODS: [15O]water and [18F]FDG-PET, and [99mTc]-HMPAO SPECT were performed in 25 patients (SPECT in 17 of 25) with medial temporal lobe epilepsy. For volume of interest (VOI) count analysis, the normalized counts using VOI based on SPAM templates of PET and SPECT were compared with those of the normal controls. Perfusion or metabolism was found abnormal if the Z score was >2 for each VOI. For SPM analysis, the differences between each patient's image and a group of normal control images (t statistic for p < 0.01) on a voxel-by-voxel basis were examined to find significant decreases in perfusion or metabolism. RESULTS: With SPAM VOI count analysis, areas of hypoperfusion were found in 13 patients in the epileptogenic temporal lobes by [15O]water PET and areas of hypometabolism in 21 patients by [18F]FDG-PET. With voxel-based SPM analysis, the epileptogenic zones were localized in 15 by [15O]water PET and in 23 patients by [18F]FDG-PET. The localization by [15O]water PET was concordant with that of [18F]FDG-PET. The areas of hypoperfusion on [15O]water PET were absent or smaller than the areas of hypometabolism on [18F]FDG-PET. Interictal [99mTc]-HMPAO SPECT revealed the hypoperfused zones in seven of 17 patients on visual assessment. CONCLUSIONS: SPAM VOI count and SPM analysis of [15O]water and [18F]FDG-PET and [99mTc]-HMPAO SPECT revealed that in the same patients, the areas of hypoperfusion were concordant with but smaller than the areas of hypometabolism. Discordance of perfusion and metabolic abnormalities represents an uncoupling of perfusion and metabolism in the epileptogenic zones, and this might explain the lower diagnostic accuracy of perfusion imaging in temporal lobe epilepsy.     

Positron emission tomography studies of cerebral glucose metabolism in chronic partial epilepsy

Positron emission tomography (PET) performed with [18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG) was used to measure local cerebral metabolic rate for glucose (lCMRGlc) interictally in 31 patients with chronic partial epilepsy and 16 age-matched normal subjects. Hypometabolic zones were visualized in 25 patients (81%). Cortical lCMRGlc in hypometabolic zones was within 2 standard deviations of the mean for normal temporal cortex in all but 8 patients. However, in 24 patients asymmetry between the hypometabolic cortex and homologous contralateral cortex was more than 2 standard deviations above the mean cortical asymmetry for normals. There was good correlation between hypometabolic zones and electroencephalogram (EEG) foci in patients with unilateral well-defined EEG foci. Diffuse or shifting EEG abnormalities were often associated with normal PET scans. Of 28 patients who underwent magnetic resonance imaging, 10 showed focal temporal lobe abnormalities corresponding to focal hypometabolism. While the [18F]FDG PET scan cannot currently localize an epileptogenic zone independently, the absence of focal hypometabolism or its presence contralateral to a presumed EEG focus suggests the need for additional electrophysiological data.     

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Several reports have indicated that cortical resection is effective in alleviating intractable epilepsy in children with tuberous sclerosis complex (TSC). Because of the multitude of cortical lesions, however, identifying the epileptogenic tuber(s) is difficult and often requires invaise intracranial electroencephalographic (EEG) monitoring. As increased concentrations of serotonin and serotonin-immunoreactive processes have been reported in resected human epileptic cortex, we used α-[¹¹C]methyl-L-tryptophan ([¹¹C]AMT) position emission tomography (PET) to test the hypothesis that serotonin synthesis is increased interictally in epileptogenic tubers in patients with TSC. Nine children with TSC and epilepsy, aged 1 to 9 years (mean, 4 years 1 month), were studied. All children underwent scalp video-EEG monitoring, PET scans of glucose metabolism and serotonin synthesis, and EEG monitoring during both PET studies. [¹¹C]AMT scans were coregistred with magnetic resonance imaging and with glucose metabolism scans. Whereas glucose metabolism PET showed multifocal cortical hypometabolism corresponding to the locations of tubers in all 9 children, [¹¹C]AMT uptake was increased in one tuber (n = 3), two tubers (n = 3), three tubers (n = 1), and four tubers (n = 1) in 8 of the 9 children. All other tubers showed decreased [¹¹C]AMT uptake. Ictal EEG data available in 8 children showed seizure onset corresponding to foci of increased [¹¹C]AMT uptake in 4 children (including 2 with intracranial EEG recordings). In 2 children, ictal EEG was nonlocalizing, and in 1 child there was discordance between the region of increased [¹¹C]AMT uptake and the region of ictal onset on EEG. The only child whose [¹¹C]AMT scan showed to no regions of increased uptake had a left frontal seizure focus on EEG; however, at the time of his [¹¹C]AMT PET scan, his seizures had come under control. [¹¹C]AMT PET may be a powerful tool in differentiating between epileptogenic and nonepileptogenic tubers in patients with TSC.     

11 C]Flumazenil binding in the medial temporal lobe in patients with temporal lobe epilepsy: correlation with hippocampal MR volumetry, T2 relaxometry, and neuropathology

OBJECTIVE: To detect reduced [11C]flumazenil in patients with temporal lobe epilepsy (TLE) and to relate binding to histopathology. METHODS: The authors studied 16 patients who underwent epilepsy surgery because of drug-resistant TLE using [11C]flumazenil PET and quantitative MRI. In 12 patients, resected hippocampus was available for histologic analysis. [11C]Flumazenil binding potential (fitted BP) was assessed with the simplified reference tissue model. RESULTS: [11C]Flumazenil fitted BP in the medial temporal lobe was reduced in all patients with abnormal hippocampal volumetry or T2 relaxometry on MRI. Fitted BP was also reduced in 46% of the patients with hippocampal volume within the normal range and in 38% of patients with less than 2 SD T2 prolongation. In all MRI-negative/PET-positive patients, the histologic analysis verified hippocampal damage. Also, [11C]flumazenil fitted BP correlated with the severity of reduced hippocampal volume, T2 prolongation, and histologically assessed neuronal loss and astrogliosis. CONCLUSION: [11C]Flumazenil PET provides a useful tool for investigating the hippocampal damage in vivo even in patients with no remarkable hippocampal abnormalities on quantitative MRI.     

Surgical treatment of West syndrome.

The discovery of focal or multifocal cortical lesions using magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning in the majority of infants with West syndrome has led to a surgical approach in the treatment of some patients with intractable infantile spasms. The locations of these lesions should be concordant with localization of focal ictal and/or interictal electroencephalographic (EEG) abnormalities prior to proceeding with cortical resection. When a single lesion is present on the MRI or PET, and there is good correlation with EEG localization, surgical treatment is generally quite favorable in terms of both seizure control and cognitive development. Interictal glucose metabolism PET scans in children with intractable cryptogenic infantile spasms show unifocal cortical hypometabolism in about 20% of cases. In the majority, however, multifocal asymmetric hypometabolism is suggestive of multifocal underlying lesions, possibly multifocal cortical dysplasia. When the pattern of glucose hypometabolism is symmetric, a lesional etiology is less likely, thus neurometabolic or neurogenetic disorders should be considered. Therefore, the pattern of glucose hypometabolism on PET in infants with intractable cryptogenic spasms is a useful guide to decide whether a medical or surgical approach should be undertaken. In order to achieve the best cognitive outcome with surgery, it is important to resect the entire 'nociferous' area rather than just the seizure focus. Our research with new PET imaging probes has attempted to provide a comprehensive evaluation of the epileptogenic zone including the 'nociferous' cortex. We have used [(11)C]flumazenil (FMZ), which labels gamma aminobutyric acid(A) (GABA(A)) receptors, and have found this to be particularly useful in showing: (i) decreased receptor binding with medial temporal involvement thus indicating resection of medial temporal structures, (ii) the peri-lesional epileptogenic zone surrounding MRI lesions, (iii) the seizure onset zone in MRI-negative cases, and (iv) potential secondary epileptic foci. Another recently developed PET probe, alpha[(11)C]methyl-L-tryptophan (AMT) which is a precursor for the serotonin and the kynurenine metabolism pathways, is capable of differentiating between epileptogenic and non-epileptogenic tubers in patients with tuberous sclerosis complex and intractable epilepsy (including infantile spasms). Subsequently, we have applied AMT PET in patients with multifocal cortical dysplasia to determine the predominant seizure focus, and the results have been promising with regard to seizure control but not cognitive development. Thus, the introduction of newer more specific PET probes for epilepsy has led to improved and more accurate localization of seizure foci that should ultimately improve outcome of epilepsy surgery in West syndrome.     

Comparison of [11C]flumazenil and [18F]FDG as PET markers of epileptic foci.

Recent PET results indicate that the benzodiazepine (BZ) receptor density measured with the BZ receptor antagonist [11C]flumazenil is reduced in human epileptic foci. The present study examines the applicability of this finding in the presurgical investigation of patients with intractable partial epilepsy. In eight patients, the PET measurements were performed after injection of the BZ receptor antagonist [11C]flumazenil and [2-18F]2-deoxy-2-fluoro-D-glucose ([18F]FDG)--a tracer for measurements of the rate of regional glucose metabolism. The focus localising ability of the two PET tracers was examined using extra--and intracranial EEG recordings as reference. The focus was first determined visually on the PET images obtained after a bolus injection of each of the PET tracers. Its anatomical localisation and spatial delimitation was then evaluated for each patient with a computerised anatomical brain atlas. [11C]flumazenil was found to be a more sensitive and accurate focus localiser than [18F]FDG. This observation was valid both for quantified and non-quantified images. In the preoperative diagnosis of epileptic foci, the PET measurements of BZ receptors may be a suitable and, in some cases, superior method to the generally used "[18F]FDG-PET" method.     

Neuroimaging of epilepsy

It can sometimes be difficult, when examining surgical specimens, to detect underlying pathological abnormalities that may account for disordered electrical activity. For accurate diagnosis, neuropathologists and clinicians need to share common preoperative information about resected brain tissue. Our group has been able to use structural, functional, and electrophysiological neuroimaging techniques to visualize epileptogenic areas preoperatively. MRI is the most sensitive and useful examination to demonstrate structural abnormalities in patients with partial or localization‐related epilepsy. Temporal lobe epilepsy, neoplastic lesions, vascular lesions, and developmental anomaly can all be surgically corrected under favorable circumstances. Functional neuroimaging by positron emission tomography (PET) and single‐photon emission computed tomography (SPECT) are useful tools for detecting epileptic foci. PET and SPECT demonstrate subtle functional changes related to epilepsy that ultimately may enable the detection of epileptogenic areas invisible to MRI. PET/SPECT images coregistered to MRI and statistical parametric mappings are of more value for detecting than PET/SPECT images alone. Electrophysiological neuroimaging with analytical software is very useful for visually understanding epileptogenic phenomena. Computerized voltage topographic mappings overlapped on three‐dimensional MRI with multichannel electrodes visually demonstrate ictal onset areas and seizure propagation. A new method of multimodal image‐guided intervention enables the detection of epileptogenic areas by electrocorticography, PET images, and MRI during epilepsy surgery. Neuropathologists using this method can collect precise structural, functional, and electrophysiological findings on surgical specimens. Neuroimaging of epilepsy is useful for visually clarifying structural, functional, and electrophysiological information on epilepsy patients. This approach is key for diagnosing the background pathological abnormalities of resected tissue.