Faculty Bibliography

In children with partial epilepsy, there is increasing evidence to suggest that not all cortical regions showing glucose hypometabolism on positron emission tomography (PET) represent epileptogenic cortex but that some hypometabolic areas might be the result of repeated seizures. Most of the supportive data, however, have come from cross-sectional imaging studies. To evaluate longitudinal changes in cortical glucose hypometabolism, we compared two sequential [(18)F]fluorodeoxyglucose (FDG) PET scans performed 7 to 44 months apart in 15 children with intractable nonlesional partial epilepsy. The extent of hypometabolic cortex on the side of the electroencephalography-verified epileptic focus and its changes between the two PET scans were measured and correlated to clinical seizure variables. The change in seizure frequency between the two PET scans correlated positively with the change in the extent of cortical glucose hypometabolism (r = .8, P <.001). Most patients with persistent or increased seizure frequency (one or more seizures per day) showed enlargement in the area of hypometabolic cortex on the second PET scan. In contrast, patients whose seizure frequency had decreased below daily seizures between the first and second PET scans showed a decrease in the size of the hypometabolic cortex. These results support the notion that the extent of cortical glucose hypometabolism on PET scanning can undergo dynamic changes, and these are, at least partly, related to the frequency of seizures. The findings have implications on how aggressively persistent seizures should be treated in children. (J Child Neurol 2006;21:26-31).

PURPOSE/OBJECTIVE:Previous studies using diffusion MRI in patients with temporal lobe epilepsy have shown abnormal water diffusion in the hippocampus. Because thalamus and lentiform nuclei are considered important for the regulation of cortical excitability and seizure propagation, we analyzed diffusion tensor imaging (DTI) abnormalities in these subcortical structures and in hippocampus of children with partial epilepsy with and without secondary generalization. METHODS:Fourteen children with partial epilepsy involving the temporal lobe underwent MRI including a DTI sequence. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained in the hippocampus, thalamus, and lentiform nucleus, and compared with DTI data of 14 control children with no epilepsy, as well as glucose positron emission tomography (PET) findings. RESULTS:Decreased FA (p < 0.001) and increased ADC (p = 0.003) values were found in the hippocampi ipsilateral to the seizure focus. Significant FA decreases (p = 0.002) also were seen in the contralateral hippocampi, despite unilateral seizure onset and excellent surgical outcome in patients who underwent surgery. ADC values showed a trend for increase in the thalami ipsilateral to the epileptic focus in the seven children with secondarily generalized seizures (p = 0.09). No group differences of ADC or FA were found in the lentiform nuclei. The DTI variables did not correlate with regional glucose metabolism in any of the structures analyzed. CONCLUSIONS:Increased ADC values in hippocampus can assist in lateralizing the seizure focus, but decreased FA in the contralateral hippocampus suggests that it too may be dysfunctional despite unilateral seizure onset. Less-robust thalamic abnormalities of water diffusion in patients with secondarily generalized seizures suggest secondary involvement of the thalamus, perhaps due to recruitment of this structure into the epileptic network; however, this must be confirmed in a larger population. DTI appears to be a sensitive method for detection abnormalities in children with partial epilepsy, even in structures without apparent changes on conventional MRI.

Advances in positron emission tomography (PET) techniques have allowed the measurement and imaging of neurotransmitter synthesis, transport, and receptor binding to be performed in vivo. With regard to epileptic disorders, imaging of neurotransmitter systems not only assists in the identification of epileptic foci for surgical treatment, but also provides insights into the basic mechanisms of human epilepsy. Recent investigative interest in epilepsy has focused on PET imaging of tryptophan metabolism, via the serotonin and kynurenine pathways, as well as on imaging of serotonin receptors. This review summarizes advances in PET imaging and how these techniques can be applied clinically for epilepsy treatment.

Epilepsy is a disease of recurrent seizures that can develop after a wide range of brain insults. Although surgical resection of focal regions of seizure onset can result in clinical improvement, the molecular mechanisms that produce and maintain focal hyperexcitability are not understood. Here, we demonstrate a regional, persistent induction of a common group of genes in human epileptic neocortex in 17 patients with neocortical epilepsy, regardless of the underlying pathology. This relatively small group of common genes, identified using complementary DNA microarrays and confirmed with quantitative reverse transcription polymerase chain reaction and immunostaining, include the immediate early gene transcription factors EGR-1, EGR-2, and c-fos, with roles in learning and memory, and signaling genes such as the dual-specificity kinase/phosphatase MKP-3. Maximal expression of these genes was observed in neurons in neocortical layers II through IV. These neurons also showed persistent cyclic adenosine monophosphate response element binding protein (CREB) activation and nuclear translocation of EGR-2 and c-fos proteins. In two patients, local interictal epileptiform discharge frequencies correlated precisely with the expression of these genes, suggesting that these genes either are directly modulated by the degree of epileptic activity or help sustain ongoing epileptic activity. The identification of a common set of genes and the persistent activation of CREB signaling in human epileptic foci provide a clinically relevant set of biological markers with potential importance for developing future diagnostic and therapeutic options in human epilepsy.

We studied the relationship between brain glucose metabolism patterns and objectively measured interictal epileptiform abnormalities in six children with intractable epilepsy and continuous spike-and-wave activity during slow-wave sleep. Five of the six patients showed lateralized positron emission tomographic (PET) findings, with the hemisphere showing a relative increase in glucose metabolism concordant with the presumed origin of the generalized interictal spike activity delineated by quantitative electroencephalographic (EEG) analysis. One of these five patients achieved seizure freedom following cortical resection involving the areas of unilateral multifocal hypermetabolism, and another patient has been approved for cortical resection. The results in the present study add further support to the hypothesis that the generalized spike-waves in most cases of continuous spike-and-wave activity during slow-wave sleep are the result of secondary bilateral synchrony. Resective surgery can be effective in selected patients with uncontrolled seizures associated with continuous spike-and-wave activity during slow-wave sleep provided that there is concordance between focal abnormalities on PET and EEG.

OBJECTIVE:We retrospectively reviewed the clinical utility of initial video-EEG monitoring in a series of 1000 children suspected of epileptic disorders. METHODS:The ages of patients (523 boys and 477 girls) ranged from 1 month to 17 years (median age: 7 years). The mean length of stay was 1.5 days (range: 1-10 days). Outcomes were classified as: 'useful-epileptic' (successful classification of epilepsy), 'useful-nonepileptic' (demonstration of nonepileptic habitual events), 'uneventful' (normal EEG without habitual events captured), and 'inconclusive' (inability to clarify the nature of habitual events with abnormal interictal EEG findings). RESULTS:A total of 315 studies were considered 'useful-epileptic'; 219 'useful-nonepileptic'; 224 'uneventful'; 242 'inconclusive'. Longer monitoring was associated with higher rate of a study classified as 'useful-epileptic' in all age groups (Chi square test: p<0.001). In addition, longer monitoring was associated with lower rate of a study classified as 'inconclusive' in adolescences (p<0.001). Approximately half of the children with successful classification of epilepsy were assigned a specific diagnosis of epilepsy syndrome according to the International League Against Epilepsy (ILAE) classification. We found only 22 children with ictal EEG showing a seizure onset purely originating from a unilateral temporal region. CONCLUSION/CONCLUSIONS:Video-EEG monitoring may fail to capture habitual episodes. To maximize the utility of studies in the future, a video-EEG monitoring longer than 3 days should be considered in selected children such as adolescences with habitual events occurring on a less than daily basis. We recognize a reasonable clinical utility of the current ILAE classification in the present study. It may not be common to identify children with pure unilateral temporal lobe epilepsy solely based on video-EEG monitoring.

PURPOSE/OBJECTIVE:Ictal electrographic changes were analyzed on intracranial electrocorticography (ECoG) in children with medically refractory epileptic spasms to assess the dynamic changes of ictal discharges associated with spasms and their relation to interictal epileptiform activity and neuroimaging findings. METHODS:We studied a consecutive series of 15 children (age 0.4 to 13 years; nine girls) with clusters of epileptic spasms recorded on prolonged intracranial subdural ECoG recordings, which were being performed for subsequent cortical resection, and in total, 62 spasms were analyzed by using quantitative methods. RESULTS:Spasms were associated with either a "leading" spike followed by fast-wave bursts (type I: 42 events analyzed quantitatively) or fast-wave bursts without a "leading" spike (type II: 20 events analyzed quantitatively). Twenty-three of the 42 type I spasms but none of the 20 type II spasms were preceded by a focal seizure. A "leading" spike had a focal origin in all 42 type I spasms and involved the pre- or postcentral gyrus within 0.1 s in 37 of these spasms. A leading spike was associated with interictal spike activity >1/min in 40 of 42 type I spasms and originated within 2 cm from a positron emission tomography glucose hypometabolic region in all but two type I spasms. Failure to resect the cortex showing a leading spike was associated with poor surgical outcome (p = 0.01; Fisher's exact probability test). Fast-wave bursts associated with spasms involved neocortical regions extensively at least in two lobes within 1.28 s in all 62 spasms and involved the pre- or postcentral gyrus in 53 of 62 spasms. CONCLUSIONS:Epileptic spasms may be triggered by a focal neocortical impulse in a subset of patients, and a leading spike, if present, might be used as a marker of the trigger zone for epileptic spasms. Rapidly emerging widespread fast-wave bursts might explain the clinical semiology of epileptic spasms.

An improved one-pot synthesis procedure for routine production of [carbonyl-(11)C]desmethyl-WAY-100635 ([(11)C]DWAY) is described. An efficient purification of the crude product has also been developed and was accomplished by C-18 reversed-phase semi-preparative HPLC using 55/45 EtOH-NaH(2)PO(4) buffer (20 mM, pH=6.5) as the eluent. The desired product fraction was collected in a 2.0-2.5 mL volume and formulated with 11 mL of 0.9% saline. The radioligand was ready for human use in 45 min (EOB). The product was obtained with a radiochemical yield of 11.1+/-1.8% (EOB, n=15) with a radiochemical purity of >99%. Specific activity was 133.2-185.0 GBq/micromol (3.6-5.0 Ci/micromol, EOS, n=2) when ca. 37.0 GBq (ca. 1.0 Ci) of starting [(11)C]CO(2) was used. Unlabeled mass of [(11)C]DWAY was found to be 0.15-0.24 microg/mL and the precursor was present in less than 50 ng/mL in final production solution.

Tuberous sclerosis complex is commonly associated with medically intractable seizures. We previously demonstrated that high uptake of alpha-[11C]methyl-L-tryptophan (AMT) on positron emission tomography (PET) occurs in a subset of epileptogenic tubers consistent with the location of seizure focus. In the present study, we analyzed the surgical outcome of children with tuberous sclerosis complex in relation to AMT PET results. Seventeen children (mean age 4.7 years) underwent epilepsy surgery, guided by long-term videoelectroencephalography (EEG) (including intracranial EEG in 14 cases), magnetic resonance imaging (MRI), and AMT PET. AMT uptake values of cortical tubers were measured using regions of interest delineated on coregistered MRI and were divided by the value for normal-appearing cortex to obtain an AMT uptake ratio. Based on surgical outcome data, tubers showing increased AMT uptake (uptake ratio greater than 1.00) were classified into three categories: (1) epileptogenic (tubers within an EEG-defined epileptic focus whose resection resulted in seizure-free outcome), (2) nonepileptogenic (tubers that were not resected but the patient became seizure free), or (3) uncertain (all other tubers). Increased AMT uptake was found in 30 tubers of 16 children, and 23 of these tubers (77%) were located in an EEG-defined epileptic focus. The tuber with the highest uptake was located in an ictal EEG onset region in each patient. Increased AMT uptake indicated an epileptic region not suspected by scalp EEG in four cases. Twelve children (71%) achieved seizure-free outcome (median follow-up 15 months). Based on outcome criteria, 19 of 30 tubers (63%) with increased AMT uptake were epileptogenic, and these tubers had significantly higher AMT uptake than the nonepileptogenic ones (P = .009). Tubers with at least 10% increase of AMT uptake (in nine patients) were all epileptogenic. Using a cutoff threshold of 1.02 for AMT uptake ratio provided an optimal accuracy of 83% for detecting tubers that needed to be resected to achieve a seizure-free outcome. The findings suggest that resection of tubers with increased AMT uptake is highly desirable to achieve seizure-free surgical outcome in children with tuberous sclerosis complex and intractable epilepsy. AMT PET can provide independent complementary information regarding the localization of epileptogenic regions in tuberous sclerosis complex and enhance the confidence of patient selection for successful epilepsy surgery.