Quantifying interictal metabolic activity in human temporal lobe epilepsy.

The majority of patients with complex partial seizures of unilateral temporal lobe origin have interictal temporal hypometabolism on [18F]fluorodeoxyglucose positron emission tomography (FDG PET) studies. Often, this hypometabolism extends to ipsilateral extratemporal sites. The use of accurately quantified metabolic data has been limited by the absence of an equally reliable method of anatomical analysis of PET images. We developed a standardized method for visual placement of anatomically configured regions of interest on FDG PET studies, which is particularly adapted to the widespread, asymmetric, and often severe interictal metabolic alterations of temporal lobe epilepsy. This method was applied by a single investigator, who was blind to the identity of subjects, to 10 normal control and 25 interictal temporal lobe epilepsy studies. All subjects had normal brain anatomical volumes on structural neuroimaging studies. The results demonstrate ipsilateral thalamic and temporal lobe involvement in the interictal hypometabolism of unilateral temporal lobe epilepsy. Ipsilateral frontal, parietal, and basal ganglial metabolism is also reduced, although not as markedly as is temporal and thalamic metabolism.

Butanol is superior to water for performing positron emission tomography activation studies.

[15(O)]Butanol has been shown to be superior to [15(O)]water for measuring cerebral blood flow with positron emission tomography. This work demonstrates that it is also superior for performing activation studies. Data were collected under three conditions: a visual confrontation animal-naming task, nonsense figure size discrimination, and a nonvisual darkroom control task. Time-activity curves (TAC) were obtained for regions known to be activated by the confrontation naming task to compare absolute uptake and the different kinetics of the two tracers. Also, t statistic maps were calculated from the data of 10 subjects for both tracers and compared for magnitude of change and size of activated regions. Peak uptake in the whole-brain TAC were similar for the two tracers. For all regions and conditions, the washout rate of [15(O)]butanol was 41% greater than that of [15(O)]water. At a threshold of 0, the [15(O)]water and [15(O)]butanol percent difference (nonnormalized) and t statistic (global normalization) images are nearly identical, indicating that the same property is being measured with both tracers. The [15(O)]butanol parametric images displayed at a threshold of /t/ = 5 look similar to the [15(O)]water parametric maps displayed at a threshold of /t/ = 4, which is consistent with the observation that t statistic values in [15(O)]butanol images are generally greater. The t statistic values were equal when the [15(O)]butanol parametric map was created from any subset of 6 subjects and the [15(O)]water parametric map was created from all 10 subjects. Fewer subjects need to be studied with [15(O)]butanol to reach the same statistical power as an [15(O)]water-based study.

Alumina gel injections into the temporal lobe of rhesus monkeys cause complex partial seizures and morphological changes found in human temporal lobe epilepsy.

The goal of the present study was to determine whether alumina gel injections into temporal lobe structures cause complex partial seizures (CPS) and pathological changes observed in human temporal lobe epilepsy. Rhesus monkeys with alumina gel injections in the amygdala, perirhinal and entorhinal cortices, or Ammon's horn and dentate gyrus all initially displayed focal pathological electroencephalographic (EEG) slowing limited to the site of injection. After clinical seizures developed, they also displayed widespread pathological EEG slowing over both hemispheres, interictal and ictal epileptiform EEG abnormalities limited to the mesial-inferior temporal lobe on the side of injection, and different degrees of spread to other ipsilateral and contralateral structures. Noninjected control and nonepileptic monkeys with injections into the middle and inferior temporal gyri displayed no hippocampal neuronal loss or mossy fiber sprouting. When alumina gel was injected into the amygdala, CPS began within 3-6 weeks and degeneration of neurons and gliosis occurred in the perirhinal cortex or the hippocampus, with consequent sprouting of mossy fibers in the dentate gyrus. Dispersion of the granule cell layer was also observed. Other monkeys with alumina gel in the perirhinal and entorhinal cortices developed CPS within 2-3 weeks after the injections and displayed mossy fiber sprouting only after 4 weeks after the injections. Alumina gel in Ammon's horn and the dentate gyrus also induced CPS, but mossy fiber sprouting was limited to sites immediately adjacent to the injection, probably because none survived more than 4 weeks after the injections. This nonhuman primate model of CPS displayed similar anatomical, behavioral, and EEG features as observed in human temporal lobe epilepsy and provides opportunities to analyze the chronological sequence of epileptogenesis and to test potential therapies.

Interictal metabolic anatomy of mesial temporal lobe epilepsy.

OBJECTIVE--To examine patterns of temporal and extratemporal regional interictal glucose hypometabolism in individual patients with unilateral mesial temporal lobe epilepsy (TLE). Previous reports disagree on which extratemporal areas can be hypometabolic in TLE. DESIGN--Case series of patients with TLE who underwent interictal fludeoxyglucose F 18 positron emission tomography, compared quantitatively with normal positron emission tomography. SETTING--Patients referred for surgical treatment of medically refractory complex partial seizures. PATIENTS AND OTHER PARTICIPANTS--Ten normal volunteers; 27 patients with TLE selected to exclude seizures of bilateral temporal or extratemporal onset. RESULTS--Regional hypometabolism occurred in 25 patients. Hypometabolic regions were ipsilateral to seizure onset and included lateral temporal (in 78% of patients), mesial temporal (70%), thalamic (63%), basal ganglial (41%), frontal (30%), parietal (26%), and occipital (4%). Specific patterns of temporal and extratemporal hypometabolism varied considerably across the TLE group. CONCLUSIONS--Any of the previously reported anatomic areas of hypometabolism can occur in individual patients with TLE. The prevalence of thalamic hypometabolism suggests a pathophysiologic role for the thalamus in initiation or propagation of temporal lobe seizures or in the interictal cognitive dysfunction of TLE.

Asymmetric interictal glucose hypometabolism and cognitive performance in epileptic patients.

OBJECTIVE: To relate hemispheric metabolic asymmetries to cognitive performance in patients with unilateral mesial temporal lobe epilepsy. DESIGN: Asymmetrical cerebral glucose metabolisms on interictal fludeoxyglucose F 18 positron emission tomograms (FDG-PET) were correlated with cognitive measures. Analyses included partial correlations that controlled for the correlation between metabolic asymmetries of the lateral temporal lobe and other brain regions and the correlation of IQ scores with affected cognitive scores. SETTING: A university epilepsy surgery center. PATIENTS: Subjects included 13 patients who had intractable complex partial seizures originating from a mesial temporal lobe. INTERVENTION: Patients underwent FDG-PET scanning as part of their diagnostic work-up. Asymmetry indexes for cerebral metabolic rates were determined for whole hemisphere, lateral temporal lobe, mesial temporal lobe, frontal lobe, thalamus, and parietal lobe. MAIN OUTCOME MEASURES: The following cognitive domains were assessed: psychometric intelligence, mental control/attention, language, and verbal and nonverbal memory. Neuropsychological measures were obtained within 14 days of FDG-PET scanning. RESULTS: Relative reductions in glucose metabolism of the left hemisphere and left lateral temporal lobe correlated with a lower verbal IQ score and a lower score on a verbal memory task, recall of logical prose. Relative reduction in metabolism of the left side of the thalamus also correlated with lower scores for recall of logical prose. CONCLUSION: Relative hypometabolism of the left hemisphere correlates with lower cognitive performance. Hypometabolism of the left lateral temporal lobe and thalamus independently correlates with the verbal memory difficulties seen in this epileptic patient population.

Influence of head trauma on outcome following anterior temporal lobectomy.

BACKGROUND: There is controversy in the literature regarding the importance of risk factors in developing epilepsy and seizure outcome following anterior temporal lobectomy. Some of the existing studies may be biased because of patient selection and limitations in determining predisposition. OBJECTIVE: To investigate the role of risk factors for epilepsy in determining outcome following anterior temporal lobectomy. PATIENTS AND METHODS: We identified 102 patients in a consecutive surgery series for epilepsy from a tertiary center with a minimum of 1-year postoperative follow-up. Risk factors for epilepsy were determined prospectively on at least 3 occasions before anterior temporal lobectomy. Risk factors investigated were a history of febrile convulsions, family history of epilepsy, significant head trauma, history of meningitis, history of encephalitis, or significant perinatal insult. Foreign tissue lesions on magnetic resonance imaging was also included if an anterior temporal lobectomy was performed for presumed dual pathologic findings (hippocampus and lesion). Outcome was determined using Engel's classification. For statistical analysis we used successive logistic regression analysis, chi(2) test, Fisher exact test, and t test. RESULTS: Of the 102 patients, 13 had no identified risk factor for epilepsy, 49 had 1 identified risk factor, and 40 had more than 1. Frequencies were 39 febrile convulsions (15 complex febrile convulsions), 29 head trauma, 22 with lesions seen on magnetic resonance imaging, 12 history of meningitis, 2 history of encephalitis, 19 family history of epilepsy, and 4 perinatal insult. Seventy-one (70%) were classified as Engel's class I, with 56 patients continuously free of seizures at follow-up. Those without risk factor were as likely to be rendered free of seizures following anterior temporal lobectomy as those with a risk factor (P = .27). No risk factor alone or in combination was correlated with complete freedom from seizures following anterior temporal lobectomy, but the presence of head trauma, alone or in combination, was correlated with continued seizures following anterior temporal lobectomy (P = .03; odds ratio, 2.6). Better outcomes were not seen in those with head trauma before the age of 5 years (P = .57). These findings did not change if all those with lesions on magnetic resonance imaging were excluded in the analysis. Those with a history of head trauma were as likely to have pathologic evidence of mesial temporal sclerosis as others (P = .82). CONCLUSIONS: Patients with a history of significant head trauma are less likely to become free of seizures following anterior temporal lobectomy. No other risk factor correlated with a statistically significant greater or lesser chance of freedom from seizures. This information may be used in preoperative counseling of patients.

Non-epileptic seizures in temporal lobectomy candidates with medically refractory seizures.

Diagnosis of epileptic seizures is often based on temporal lobe epileptiform abnormalities appearing on interictal EEG, when reported ictal semiologies are consistent with temporal lobe seizures. It is unclear how often such patients have non-epileptic seizures. We studied 145 patients who had temporal interictal EEG spikes and reported ictal semiology characteristic of temporal lobe seizures, with long-term EEG-video-monitoring (LTM) for presurgical evaluation of medically refractory seizures. Nonepileptic seizures were unexpectedly recorded in 12 of these patients (8%). Outcomes after LTM in patients who had both epileptic seizures and nonepileptic seizures demonstrated that the epileptic seizures usually were controlled with medications. Our observations support LTM as useful in diagnosis of non-epileptic seizures in this group of patients. We suggest that ictal recordings always should be performed before epilepsy surgery, in part to avoid unintentional surgical treatment of nonepileptic seizures.

Progressive myoclonus epilepsy treated with zonisamide.

Two patients with progressive myoclonus epilepsy of the Unverricht-Lundborg type and with intractable seizures in spite of standard anticonvulsant regimens were treated with zonisamide. After zonisamide therapy was initiated, both had a marked decrease in seizure frequency and significant improvement of functioning. Serum zonisamide concentrations were 43 and 27 micrograms/ml, respectively, with doses of 8.8 and 10.5 mg/kg/d. Both patients also continue to receive valproic acid and a benzodiazepine.

Increased secondary generalization of partial seizures after temporal lobectomy.

OBJECTIVE: This study tests the primary hypothesis that secondary generalization of partial seizures is more likely after anterior temporal lobectomy (ATL) than before ATL, and the secondary hypothesis that antiepileptic drug withdrawal accounts for increased generalization of seizures postoperatively. BACKGROUND: The authors observed that some patients had generalized tonic-clonic (GTC) seizures after but not before ATL, by using a new classification of outcome that compares preoperative and postoperative seizure frequencies by seizure type. METHODS: Twenty patients with refractory temporal lobe epilepsy had postoperative GTC seizures or nongeneralizing complex partial (CP) seizures in a consecutive ATL series. All had reduced seizure frequency postoperatively and more than 2 years of follow-up on antiepileptic drugs. The authors calculated a generalization fraction, as (number of GTC seizures)/(number of CP and GTC seizures), for 2 years before and 2 years after surgery. RESULTS: Postoperative generalization fractions were greater than preoperative generalization fractions (Wilcoxon signed-rank test, p < 0.01). Most postoperative GTC seizures were not associated with antiepileptic drug withdrawal, and postoperative GTC seizures were not more associated with drug withdrawal than were postoperative CP seizures. Patients with more than two GTC seizures per year preoperatively were more likely than other patients to have postoperative GTC seizures. CONCLUSIONS: Patients with reduced seizure frequency after ATL have a greater tendency for partial seizures to secondarily generalize postoperatively. This phenomenon is not explained by antiepileptic drug withdrawal.

Ictal localization of temporal lobe seizures with scalp/sphenoidal recordings.

We assessed the reliability and accuracy of scalp/sphenodial recordings for ictal localization by retrospectively analyzing 706 noninvasive ictal recordings from 110 patients who subsequently underwent stereoencephalographic evaluation. Strictly defined unilateral temporal/sphenoidal ictal patterns correctly predicted findings of depth electrode examination in 82 to 94% of cases. These strictly defined predictive patterns could be detected with excellent interrater reliability. The patterns are misleading in only a minority of cases, but cannot be used in isolation for definite ictal localization.

Absence of normal activation of the left anterior fusiform gyrus during naming in left temporal lobe epilepsy.

Patients with left temporal lobe epilepsy (TLE) often have impaired naming. We studied 13 patients with left TLE and 10 healthy control subjects with [(15)O]H2O PET during visual confrontation naming. Statistical mapping detected multiple regions of significant cerebral blood flow increases within individuals. The left fusiform gyrus was activated in nine healthy subjects, but only in two patients with TLE (a significant difference, p < 0.001). Other activation sites were more variable in healthy subjects and those with TLE. Impaired naming ability may be associated with a lack of increased cerebral blood flow in the left fusiform gyrus in TLE.

Temporal lobe central benzodiazepine binding in unilateral mesial temporal lobe epilepsy.

PET-demonstrated decreases in [11C]flumazenil binding occur in anterior mesial temporal structures on the side of epileptogenesis in unilateral mesial temporal lobe epilepsy. We performed quantitative autoradiography on anterior mesial and lateral temporal specimens from 11 subjects with unilateral mesial temporal lobe epilepsy and six neurologically normal controls to identify the predominant in vitro correlates of the decreased [11C]flumazenil binding. In anterior mesial temporal regions exhibiting the greatest neuronal cell loss, decreases in agonist and antagonist binding to type 1 and 2 (central) benzodiazepine binding sites were highly correlated with neuronal cell counts. Cell loss and decreased binding were particularly prominent in the lateral portion of hippocampal region CA1, adjacent to CA2. Lateral temporal central benzodiazepine binding was diffusely increased, achieving statistical significance in cortical laminae V and VI. These findings suggest that the predominant source of PET-demonstrated decreases in [11C]flumazenil binding in mesial temporal epilepsy is hippocampal sclerosis, rather than down-regulation of central benzodiazepine binding sites on surviving hippocampal neurons.

Remission of intractable partial epilepsy following implantation of intracranial electrodes.

Six patients with medically intractable partial epilepsy (IPE) underwent seizure localization with intracranial EEG using intracerebral or subdural electrodes. No surgical resection was performed, but all had seizure remission ranging from 11 months to 15 years. Invasive monitoring may rarely produce remission of IPE, possibly through interruption of seizure propagation pathways.

Repetitive transcranial magnetic stimulation does not replicate the Wada test.

The authors compared inferior frontal speech arrest from repetitive transcranial magnetic stimulation (rTMS) with bilateral Wada tests in 17 epilepsy surgery candidates. Although rTMS lateralization correlated with the Wada test in most subjects, rTMS also favored the right hemisphere at a rate significantly greater than the Wada test. Postoperative language deficits were more consistent with Wada results. Available methods for inducing speech arrest with rTMS do not replicate the results of Wada tests.

Presurgical evaluation for partial epilepsy: relative contributions of chronic depth-electrode recordings versus FDG-PET and scalp-sphenoidal ictal EEG.

One hundred fifty-three patients with medically refractory partial epilepsy underwent chronic stereotactic depth-electrode EEG (SEEG) evaluations after being studied by positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and scalp-sphenoidal EEG telemetry. We carried out retrospective standardized reviews of local cerebral metabolism and scalp-sphenoidal ictal onsets to determine when SEEG recordings revealed additional useful information. FDG-PET localization was misleading in only 3 patients with temporal lobe SEEG ictal onsets for whom extratemporal or contralateral hypometabolism could be attributed to obvious nonepileptic structural defects. Two patients with predominantly temporal hypometabolism may have had frontal epileptogenic regions, but ultimate localization remains uncertain. Scalp-sphenoidal ictal onsets were misleading in 5 patients. For 37 patients with congruent focal scalp-sphenoidal ictal onsets and temporal hypometabolic zones, SEEG recordings never demonstrated extratemporal or contralateral epileptogenic regions; however, 3 of these patients had nondiagnostic SEEG evaluations. The results of subsequent subdural grid recordings indicated that at least 1 of these patients may have been denied beneficial surgery as a result of an equivocal SEEG evaluation. Weighing risks and benefits, it is concluded that anterior temporal lobectomy is justified without chronic intracranial recording when specific criteria for focal scalp-sphenoidal ictal EEG onsets are met, localized hypometabolism predominantly involves the same temporal lobe, and no other conflicting information has been obtained from additional tests of focal functional deficit, structural imaging, or seizure semiology.

Acute blood flow changes and efficacy of vagus nerve stimulation in partial epilepsy.

OBJECTIVE: To determine possible sites of therapeutic action of vagus nerve stimulation (VNS), by correlating acute VNS-induced regional cerebral blood flow (rCBF) alterations and chronic therapeutic responses. BACKGROUND: We previously found that VNS acutely induces rCBF alterations at sites that receive vagal afferents and higher-order projections, including dorsal medulla, somatosensory cortex (contralateral to stimulation), thalamus and cerebellum bilaterally, and several limbic structures (including hippocampus and amygdala bilaterally). METHODS: VNS-induced rCBF changes were measured by subtracting resting rCBF from rCBF during VNS, using [O-15]water and PET, immediately before ongoing VNS began, in 11 partial epilepsy patients. T-statistical mapping established relative rCBF increases and decreases for each patient. Percent changes in frequency of complex partial seizures (with or without secondary generalization) during three months of VNS compared with pre-VNS baseline, and T-thresholded rCBF changes (for each of the 25 regions of previously observed significant CBF change), were rank ordered across patients. Spearman rank correlation coefficients assessed associations of seizure-frequency change and t-thresholded rCBF change. RESULTS: Seizure-frequency changes ranged from 71% decrease to 12% increase during VNS. Only the right and left thalami showed significant associations of rCBF change with seizure-frequency change. Increased right and left thalamic CBF correlated with decreased seizures (p < 0.001). CONCLUSIONS: Increased thalamic synaptic activities probably mediate some antiseizure effects of VNS. Future studies should examine neurotransmitter-receptor alterations in reticular and specific thalamic nuclei during VNS.

In vivo cerebral metabolism and central benzodiazepine-receptor binding in temporal lobe epilepsy.

Positron emission tomography measured interictal cerebral glucose metabolism with [18F]fluorodeoxyglucose and central benzodiazepine-receptor binding with [11C]flumazenil in 10 mesial temporal lobe epilepsy (TLE) patients and in normal subjects. Eight TLE patients had mesial temporal, lateral temporal, and thalamic hypometabolism ipsilateral to EEG ictal onsets, with additional extratemporal hypometabolism in four. One had unilateral anterior mesial temporal hypometabolism only, and one had normal metabolism. Each patient had decreased benzodiazepine-receptor binding in the ipsilateral anterior mesial temporal region, without neocortical changes. Thus, interictal metabolic dysfunction is variable and usually extensive in TLE, whereas decreased central benzodiazepine-receptor density is more restricted to mesial temporal areas. Metabolic patterns in TLE may reflect diaschisis, while benzodiazepine-receptor changes may reflect localized neuronal and synaptic loss that is specific to the epileptogenic zone. [11C]Flumazenil imaging may be useful in presurgical evaluation of refractory complex partial seizures.

Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.

OBJECTIVE: The purpose of this multicenter, add-on, double-blind, randomized, active-control study was to compare the efficacy and safety of presumably therapeutic (high) vagus nerve stimulation with less (low) stimulation. BACKGROUND: Chronic intermittent left vagus nerve stimulation has been shown in animal models and in preliminary clinical trials to suppress the occurrence of seizures. METHODS: Patients had at least six partial-onset seizures over 30 days involving complex partial or secondarily generalized seizures. Concurrent antiepileptic drugs were unaltered. After a 3-month baseline, patients were surgically implanted with stimulating leads coiled around the left vagus nerve and connected to an infraclavicular subcutaneous programmable pacemaker-like generator. After randomization, device initiation, and a 2-week ramp-up period, patients were assessed for seizure counts and safety over 3 months. The primary efficacy variable was the percentage change in total seizure frequency compared with baseline. RESULTS: Patients receiving high stimulation (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency compared with a 15% reduction in the low stimulation group (102 patients, ages 15 to 60 year; p = 0.04). The high-stimulation group also had greater improvements on global evaluation scores, as rated by a blinded interviewer and the patient. High stimulation was associated with more voice alteration and dyspnea. No changes in physiologic indicators of gastric, cardiac, or pulmonary functions occurred. CONCLUSIONS: Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures. It represents the advent of a new, nonpharmacologic treatment for epilepsy.

Clinical evaluation of interictal fluorine-18-fluorodeoxyglucose PET in partial epilepsy.

Interictal [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) is useful in presurgical evaluation of medically refractory partial epilepsies. Limited replicability of image interpretation may restrict this application. We investigated interpretation replicability in 241 18F-FDG studies performed with three different tomographs in partial epilepsy patients. Two investigators independently interpreted the studies with a standardized evaluation protocol and without knowledge of the subjects. Replicability of these unbiased interpretations in detection of regional hypometabolism was best for studies performed with the highest performance tomograph. Interictal 18F-FDG studies performed with this tomograph revealed regional hypometabolism in 62% of patients who had normal cerebral magnetic resonance imaging (MRI). Replicability of interpretations in detecting regional hypometabolism was adequate for clinical application of interictal 18F-FDG studies performed with any of the tomographs.

Discordance between traditional pathologic and energy metabolic changes in very early Alzheimer's disease. Pathophysiological implications.

These results suggest that neither the loss of entorhinal efferents nor cholinergic deficit explains all the metabolic features seen in very early AD. Given recent immunohistological evidence of massive glutamatergic synaptic alteration in early AD cortex and insights into neuronal and glial mechanisms of glucose metabolism, very early metabolic changes in AD probably reflect a significant impairment of glycolytic activities in the cortico-cortical glutamatergic systems in a preclinical stage of the disease. However, the exact mechanisms of such impairment in these neurons are yet to be determined.