William H. Theodore

Standards for epidemiologic studies and surveillance of epilepsy

Worldwide, about 65 million people are estimated to have epilepsy. Epidemiologic studies are necessary to define the full public health burden of epilepsy; to set public health and health care priorities; to provide information needed for prevention, early detection, and treatment; to identify education and service needs; and to promote effective health care and support programs for people with epilepsy. However, different definitions and epidemiologic methods complicate the tasks of these studies and their interpretations and comparisons. The purpose of this document is to promote consistency in definitions and methods in an effort to enhance future population‐based epidemiologic studies, facilitate comparison between populations, and encourage the collection of data useful for the promotion of public health. We discuss: (1) conceptual and operational definitions of epilepsy, (2) data resources and recommended data elements, and (3) methods and analyses appropriate for epidemiologic studies or the surveillance of epilepsy. Variations in these are considered, taking into account differing resource availability and needs among countries and differing purposes among studies.

Functional anatomy of cognitive development fMRI of verbal fluency in children and adults

Objective: To identify age-dependent activation patterns of verbal fluency with functional MRI (fMRI). Background: Few fMRI language studies have been performed in children, and none provide comparison data to adult studies. Normative data are important for interpretation of similar studies in patients with epilepsy. Methods: A total of 10 normal children (5 boys, 5 girls; mean age, 10.7 years; range, 8.1 to 13.1 years) and 10 normal adults (5 men, 5 women; mean age, 28.7 years; range, 19.3 to 48 years) were studied on a 1.5-T Signa MRI scanner using BOLD echo planar imaging of the frontal lobes with a verbal fluency paradigm, covert word generation to letters. Studies were analyzed with a cross-correlation algorithm (r = 0.7). A region-of-interest analysis was used to determine the extent, magnitude, and laterality of brain activation. Results: Children and adults activated similar regions, predominantly in left inferior frontal cortex (Broca’s area) and left middle frontal gyrus (dorsolateral prefrontal cortex). Children had, on average, 60% greater extent of activation than adults, with a trend for greater magnitude of activation. Children also had significantly more right hemisphere and inferior frontal gyrus activation than adults. Conclusions: In a test of verbal fluency, children tended to activate cortex more widely than adults, but activation patterns for fluency appear to be established by middle childhood. Thus, functional MRI using verbal fluency paradigms may be applied to pediatric patient populations for determining language dominance in anterior brain regions. The greater activation found in children, including the right inferior frontal gyrus, may reflect developmental plasticity for the ongoing organization of neural networks, which underlie language capacity.

Noninvasive assessment of language dominance in children and adolescents with functional MRI: a preliminary study.

Background Assessment of language organization is crucial in patients considered for epilepsy surgery. In children, the current techniques, intra-carotid amobarbital test (IAT) for language dominance, and cortical electrostimulation mapping (ESM), are invasive and risky. Functional magnetic resonance imaging (fMRI) is an alternative method for noninvasive functional mapping, through the detection of the hemodynamic changes associated with neuronal activation. We used fMRI to assess language dominance in children with partial epilepsy. Methods Eleven right handed children and adolescents performed a word generation task during fMRI acquisition focused on the frontal lobes. Areas where the signal time course correlated with the test paradigm (r = 0.7) were considered activated. Extent and magnitude of signal changes were used to calculate asymmetry indices. Seven patients had IAT, ESM, or surgery outcome available for comparison. Results fMRI language dominance always agreed with IAT (6 cases) and ESM (1 case), showing left dominance in six and bilateral language in one. fMRI demonstrated left dominance in three additional children, and right dominance in one with early onset of left temporal epilepsy. Four children whose initial studies were equivocal due to noncompliance or motion artifacts were restudied successfully. Conclusions fMRI can be used to assess language lateralization noninvasively in children. It has the potential to replace current functional mapping techniques in patients, and to provide important data on brain development.

Language dominance in partial epilepsy patients identified with an fMRI reading task

Background fMRI language tasks readily identify frontal language areas; temporal activation has been less consistent. No studies have compared clinical visual judgment to quantitative region of interest (ROI) analysis. Objective To identify temporal language areas in patients with partial epilepsy using a reading paradigm with clinical and ROI interpretation. Methods Thirty patients with temporal lobe epilepsy, aged 8 to 56 years, had 1.5-T fMRI. Patients silently named an object described by a sentence compared to a visual control. Data were analyzed with ROI analysis from t-maps. Regional asymmetry indices (AI) were calculated ([L−R]/[L+R]) and language dominance defined as >0.20. t-Maps were visually rated by three readers at three t thresholds. Twenty-one patients had intracarotid amobarbital test (IAT). Results The fMRI reading task provided evidence of language lateralization in 27 of 30 patients with ROI analysis. Twenty-five were left dominant, two right, one bilateral, and two were nondiagnostic; IAT and fMRI agreed in most patients, three had partial agreement, none overtly disagreed. Interrater agreement ranged between 0.77 to 0.82 (Cramer V;p < 0.0001); agreement between visual and ROI reading with IAT was 0.71 to 0.77 (Cramer V;p < 0.0001). Viewing data at lower thresholds added interpretation to 12 patients on visual analysis and 8 with ROI analysis. Conclusions An fMRI reading paradigm can identify language dominance in frontal and temporal areas. Clinical visual interpretation is comparable to quantitative ROI analysis.

The secondarily generalized tonic‐clonic seizure A videotape analysis

We studied 120 generalized tonic-clonic seizures (GTCSs) in 47 patients with video-EEG telemetry. GTCSs were preceded by antecedent seizures, including 13 simple partial, 70 complex partial, 17 simple partial leading to complex partial, seven tonic, seven clonic, and one typical absence. We divided GTCSs into the following phases: onset of generalization, pretonic clonic, tonic, tremulousness, and clonic. The mean GTCS duration was 62 seconds. There was a nonsignificant trend toward longer duration on reduced antiepileptic drug doses. Marked heterogeneity in GTCS phenomenology was present; only 27% of seizures included all five phases. Individual phase duration and clinical expression, including tonic and clonic phases, was highly variable. The clinical phenomena suggest that multiple cortical and subcortical routes of spread may exist. When GTCSs last longer than 2 minutes, intravenous antiepileptic drug treatment should be initiated.

Hippocampal atrophy, epilepsy duration, and febrile seizures in patients with partial seizures

Background: Previous studies have suggested a variety of factors that may be associated with the presence of hippocampal formation (HF) atrophy in patients with complex partial seizures (CPS), including a history of complex or prolonged febrile seizures (FS), age at seizure onset, and epilepsy duration. Objective: To determine whether epilepsy duration is related to HF atrophy. Methods: We performed MRIs on 35 patients with uncontrolled CPS who had temporal lobe ictal onset on video-EEG. None had evidence for an alien tissue lesion or extra-hippocampal seizure onset. All had a history of secondary generalization. Brain structures were drawn on consecutive images and pixel points summed from successive pictures to calculate volumes. Results: Nine patients with a history of complex or prolonged FS had smaller ipsilateral HF volume and ipsilateral/contralateral ratio than did patients without a history of FS. Epilepsy duration had a significant relation to ipsilateral HF volume and ipsilateral/contralateral ratio. In a multivariate analysis, the effect of duration, but not age at onset or scan, was significant. Patients with a history of FS did not have earlier age at epilepsy onset or longer duration. Conclusions: A history of FS predicted the severity of HF atrophy in our patients. Age at onset or study was not a significant factor. Epilepsy duration, however, did have a significant effect, suggesting that, after an initial insult, progressive HF damage may occur in patients with persistent seizures.

Functional MRI during word generation, using conventional equipment: A potential tool for language localization in the clinical environment

Objective: To test the accuracy of bilateral language mapping using a standard clinical magnetic resonance (MR) imaging device during word generation. Design. A study of normal volunteers. Setting. Volunteers from the Washington, DC, area. Participants. Nine normal, right-handed, native English speakers (four women, five men, mean age 31 years). Interventions. During four MR acquisition periods, subjects would alternately rest and silently generate words. Sagittal MR images covered the middle and inferior frontal gyri, insulae, and part of the temporal and parietal lobes bilaterally. Main outcome measures. (1) Anatomic maps of task-related signal changes obtained by comparing, in each voxel, the signal during word generation and rest periods, and (2) analysis of the time course of the signal. Results. Maximum responses were in the left hemisphere, mainly in the frontal lobe (Brocas area, premotor cortex, and dorsolateral prefrontal cortex) but also in posterior regions such as Wernickes area. In agreement with previous studies, some degree of task-related changes was present in a subset of the corresponding regions in the right hemisphere. Conclusion. Despite certain limitations, it is possible, using widely available MR equipment, to obtain results consistent with previous studies. The technique may have important implications for assessment of cognitive functions in patients with neurologic disorders in a clinical environment. NEUROLOGY 1995;45: 1821-1827

Transcranial magnetic stimulation for the treatment of seizures A controlled study

ObjectiveTo perform a controlled trial of transcranial magnetic stimulation (TMS). MethodsTwenty-four patients with localization-related epilepsy were randomized to blinded active or placebo stimulation. Weekly seizure frequency was compared for 8 weeks before and after 1 week of 1-Hz TMS for 15 minutes twice daily. ResultsWhen the 8-week baseline and post-stimulation periods were compared, active patients had a mean seizure frequency reduction of 0.045 ± 0.13 and sham-stimulated control subjects −0.004 ± 0.20. Over 2 weeks, actively treated patients had a mean reduction in weekly seizure frequency of 0.16 ± 0.18 and sham-stimulated control subjects 0.01 ± 0.24. Neither difference was significant. ConclusionThe effect of TMS on seizure frequency was mild and short lived.

fMRI language task panel improves determination of language dominance.

Background: fMRI language tasks reliably identify language areas in presurgical epilepsy patients, but activation using single paradigms may disagree with the intracarotid amobarbital test (IAT). Objective: To determine whether a panel of fMRI tasks targeting different aspects of language processing increases accuracy in determining hemisphere language dominance. Methods: Twenty-six patients age 12 to 56 years, predominantly with temporal lobe epilepsy, were studied using whole-brain 1.5 T fMRI (echo planar imaging, blood oxygenation level–dependent) with three task categories using a block design: verbal fluency, reading comprehension, and auditory comprehension. fMRI t maps were visually rated at three thresholds. All patients had assessment of language lateralization by IAT. Results: fMRI showed left dominance in 21 patients, right dominance in 2, and bilateral activation in 2; raters disagreed over a left vs right bilateral rating in 1 patient. There was full agreement between IAT and fMRI in 21 of 25 patients (IAT failed in 1). In three instances of partial disparity with IAT, the fMRI panel showed consistent findings across raters. Agreement between raters was excellent (partial disagreement in only one patient); the panel of tasks was superior to any single task for interrater agreement (Cramer V 0.93 [range 0.91 to 1.0] vs 0.72 [range 0.60 to 0.86]). Conclusions: A panel of fMRI language paradigms may be more accurate for evaluating partial epilepsy patients than a single task. A panel of tasks reduces the likelihood of nondiagnostic findings, improves interrater reliability, and helps confirm language laterality.

PET imaging of 5-HT1A receptor binding in patients with temporal lobe epilepsy

Background: Activation of central serotonin (5-HT)1A receptors, found in high density in brainstem raphe, hippocampus, and temporal neocortex, exerts an anticonvulsant effect in various experimental seizure models. To test the hypothesis that 5-HT1A receptor binding is reduced in human epileptic foci, PET imaging was performed using the radioligand [18F]trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide ([18F]FCWAY), a selective 5-HT1A receptor antagonist, in patients with temporal lobe epilepsy and normal controls. Methods: MRI and PET were performed using [15O]water and [18F]FCWAY in 10 controls and in 12 patients with temporal lobe epilepsy confirmed on ictal video-EEG; patients also underwent [18F]fluorodeoxyglucose PET. Using quantitative PET image analysis, regional values were obtained for [18F]FCWAY volume of distribution (V), cerebral blood flow (CBF), and glucose cerebral metabolic rate (CMRglc). Hippocampal volume (HV) was also measured with MRI. [18F]FCWAY V PET and MR measures were compared within patients and controls using paired t-tests; grouped comparisons were made with two sample t-tests. Results: Lower [18F]FCWAY V was found ipsilateral than contralateral to the epileptic focus in inferior medial (IMT) and lateral (ILT) temporal regions of patients (ILT 47.4 ± 6.1 vs 61.8 ± 6.1, p < 0.01; IMT 52 ± 4.6 vs 67.0 ± 6.0, p < 0.01). [18F]FCWAY V was 29% lower in raphe and 34% lower in the ipsilateral thalamic region of patients than controls. In ILT, mean [18F]FCWAY V asymmetry index (AI) was significantly greater than mean CBF and mean CMRglc AI. Mean [18F]FCWAY V AI in IMT was greater than mean HV AI, but the difference was not significant. Conclusion: These findings support the hypothesis of reduced serotonin receptor binding in temporal lobe epileptic foci.