Faculty Bibliography

Positron emission tomography (PET) is a technique that enables imaging of the distribution of radiolabeled tracers designed to track biochemical and molecular processes in the body after intravenous injection or inhalation. New strategies for the use of radiolabeled tracers hold potential for imaging gene expression in the brain during development and following interventions. In addition, PET may be key in identifying the physiological consequences of gene mutations associated with mental retardation. The development of high spatial resolution microPET scanners for imaging of rodents provides a means for longitudinal study of transgenic mouse models of genetic disorders associated with mental retardation. In this review, we describe PET methodology, illustrate how PET can be used to delineate biochemical changes during brain development, and provide examples of how PET has been applied to study brain glucose metabolism in Rett syndrome, serotonin synthesis in autism, and GABAA receptors in Angelman's syndrome and Prader-Willi syndrome. Future application of PET scanning in the study of mental retardation might include measurements of brain protein synthesis in fragile X syndrome and tuberous sclerosis complex, two common conditions associated with mental retardation in which cellular mechanisms involve dysregulation of protein synthesis. Mental retardation results in life-long disability, and application of new PET technologies holds promise for a better understanding of the biological underpinnings of mental retardation, with the potential to uncover new treatment options.

OBJECTIVE:To quantify the ictal subdural electroencephalogram (EEG) changes using spectral analysis, and to delineate the quantitatively defined ictal onset zones on high-resolution 3D MR images in children with intractable neocortical epilepsy. METHODS:Fourteen children with intractable neocortical epilepsy (age: 1-16 years) who had subsequent resective surgery were retrospectively studied. The subjects underwent a high-resolution MRI and prolonged subdural EEG recording. Spectral analysis was applied to 3 habitual focal seizures. After fast Fourier transformation of the EEG epoch at ictal onset, an amplitude spectral curve (square root of the power spectral curve) was created for each electrode. The EEG magnitude of ictal rhythmic discharges was defined as the area under the amplitude spectral curve within a preset frequency band including the ictal discharge frequency, and calculated for each electrode. The topography mapping of ictal EEG magnitude was subsequently displayed on a surface-rendered MRI. Finally, receiver operating characteristic (ROC) analysis was performed to evaluate the consistency between quantitatively and visually defined ictal onset zones. RESULTS:The electrode showing the maximum of the averaged ictal EEG magnitude was part of the visually defined ictal onset zone in all cases. ROC analyses demonstrated that electrodes showing >30% of the maximum of the averaged ictal EEG magnitude had a specificity of 0.90 and a sensitivity of 0.74 for the concordance with visually defined ictal onset zones. SIGNIFICANCE/CONCLUSIONS:Quantitative ictal subdural EEG analysis using spectral analysis may supplement conventional visual inspection in children with neocortical epilepsy by providing an objective definition of the onset zone and its simple visualization on the patient's MRI.

PURPOSE/OBJECTIVE:Intractable focal epilepsy is commonly associated with cortical glucose hypometabolism on interictal 2-deoxy-2[18F]-fluoro-D-glucose (FDG) positron emission tomography (PET). However, subcortical brain structures also may show hypometabolism on PET and volume changes on magnetic resonance imaging (MRI) studies, and these are less well understood in terms of their pathophysiology and clinical significance. In the present study, we analyzed alterations of glucose metabolism in subcortical nuclei and hippocampus by using FDG-PET in young patients with intractable epilepsy. METHODS:Thirty-seven patients (mean age, 7.5 years; age range, 1-27 years) with intractable frontal (n = 23) and temporal (n = 14) lobe epilepsy underwent FDG-PET scanning as part of their presurgical evaluation. Normalized glucose metabolism was measured in the thalamus and caudate and lentiform nuclei, as well as in hippocampus, both ipsi- and contralateral to the epileptic focus, and correlated with duration and age at onset of epilepsy, presence or absence of secondary generalization, location of the epileptic focus, and extent of cortical glucose hypometabolism. RESULTS:Long duration of epilepsy was associated with lower glucose metabolism in the ipsilateral thalamus and hippocampus. Duration of epilepsy was a significant predictor of ipsilateral thalamic glucose metabolism in both temporal and frontal lobe epilepsy. Presence of secondarily generalized seizures also was associated with lower normalized metabolism in the ipsilateral thalamus and hippocampus. Extent of cortical hypometabolism did not correlate with subcortical metabolism, and glucose metabolism in the caudate and lentiform nuclei did not show any correlation with the clinical variables. CONCLUSIONS:The findings suggest that metabolic dysfunction of the thalamus ipsilateral to the seizure focus may become more severe with long-standing temporal and frontal lobe epilepsy, and also with secondary generalization of seizures.

PURPOSE/OBJECTIVE:To study the relation between the spike frequency during intraoperative electrocorticography (ECoG) under general anesthesia with isoflurane and that during extraoperative ECoG monitoring in children with intractable neocortical epilepsy. METHODS:Twenty-one children (age, 1-16 years; 15 boys and six girls) who underwent intraoperative and extraoperative ECoG monitoring with subdural electrode arrays were studied. The spike frequency and the spatial pattern of spike frequency were compared between intraoperative and extraoperative ECoGs for each patient (by using Wilcoxon signed-ranks and Spearman's rank correlation, respectively). RESULTS:In 15 of 21 patients, the spike frequency was significantly lower during intraoperative than during extraoperative ECoG (mean z = -6.3; p < 0.001). In four of 21 patients, no significant difference was found in the spike frequency between intraoperative and extraoperative recordings. In two of 21 patients, spike frequency reached one spike/min neither during intraoperative nor extraoperative recording; therefore appropriate comparison of spike frequency was not possible. A significant positive correlation in the spike-frequency pattern was seen between intraoperative and extraoperative recordings in nine of nine cases who had > or = 10 spikes/min during intraoperative ECoG (mean rho = 0.62; p < 0.01), in five of six cases with one to nine spikes/min (mean rho = 0.50; p < 0.01), and in none of five cases with less than one spike/min (mean rho = 0.13). CONCLUSIONS:General anesthesia often decreases the spike frequency in children with neocortical epilepsy, yet intraoperative ECoG can reliably reflect the awake interictal spiking pattern when spike frequency exceeds one spike/min during intraoperative ECoG recording.

PURPOSE/OBJECTIVE:Reoperation after failed cortical resection can alleviate seizures in patients with intractable neocortical epilepsy, provided that previously nonresected epileptic regions are accurately defined and removed. Most imaging modalities have limited value in identifying such regions after a previous surgery. Positron emission tomography (PET) using alpha-[11C]methyl-L-tryptophan (AMT) can detect epileptogenic cortical areas as regions with increased tracer uptake. This study analyzed whether increased cortical AMT uptake can detect nonresected epileptic foci in patients with previously failed neocortical resection. METHODS:Thirty-three young patients (age 3-26 years; mean age, 10.8 years) with intractable epilepsy of neocortical origin, and a previously failed cortical resection performed at various epilepsy centers, underwent further presurgical evaluation for reoperation. AMT-PET scans were performed 6 days to 7 years after the first surgery. Focal cortical areas with increased AMT uptake were objectively identified and correlated to ictal EEG data as well as clinical variables (age, postsurgical time, etiology). RESULTS:Cortical increases of AMT uptake were detected on the side of the previous resections in 12 cases. In two patients scanned shortly (within a week) after surgery, diffuse hemispheric increases were observed, without any further localization value. In contrast, in 10 (43%) of 23 patients scanned >2 months but within 2.3 years after surgery, focal cortical increases occurred, concordant with seizure onset on ictal EEG. Age, etiology (lesional vs. cryptogenic), epileptiform EEG activity during PET, or time of the last seizure were not significantly related to the presence of increased AMT uptake. All patients with localizing AMT-PET, who underwent reoperation, became seizure free (n = 5) or showed considerable improvement of seizure frequency (n = 2). CONCLUSIONS:AMT-PET can identify nonresected epileptic cortex in patients with a previously failed neocortical epilepsy surgery and, with proper timing for the scan, can assist in planning reoperation.