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Objective Presurgical language assessment can help minimize damage to eloquent cortex during resective epilepsy surgery. Two methods for presurgical language mapping are functional MRI (fMRI) and direct cortical stimulation (DCS) of implanted subdural electrodes. We compared fMRI results to DCS to help optimize noninvasive language localization and assess its validity. Methods We studied 19 patients referred for presurgical evaluation of drug-resistant epilepsy. Patients completed four language tasks during preoperative fMRI. After subdural electrode implantation, we used DCS to localize language areas. For each stimulation site, we determined whether language positive electrode pairs intersected with significant fMRI activity clusters for language tasks. Results Sensitivity and specificity depended on electrode region of interest radii and statistical thresholding. For patients with at least one language positive stimulation site, an auditory description decision task provided the best trade-off between sensitivity and specificity. For patients with no language positive stimulation sites, fMRI was a dependable method of excluding eloquent language processing. Interpretation Language fMRI is an effective tool for determining language lateralization before electrode implantation and is especially useful for excluding unexpected critical language areas. It can help guide subdural electrode implantation and narrow the search for eloquent cortical areas by DCS. Ann Neurol 2017;81:526-537.

For unknown reasons, placebos reduce seizures in clinical trials in many patients. It is also unclear why some drugs showing statistical superiority to placebo in one trial may fail to do so in another. Using Seizuretracker.com, a patient-centered database of 684,825 seizures, we simulated "placebo" and "drug" trials. These simulations were employed to clarify the sources of placebo effects in epilepsy, and to identify methods of diminishing placebo effects. Simulation 1 included 9 trials with a 6-week baseline and 6-week test period, starting at time 0, 3, 6…24 months. Here, "placebo" reduced seizures regardless of study start time. Regression-to-the-mean persisted only for 3 to 6 months. Simulation 2 comprised a 6-week baseline and then 2 years of follow-up. Seizure frequencies continued to improve throughout follow-up. Although the group improved, individuals switched from improvement to worsening and back. Simulation 3 involved a placebo-controlled "drug" trial, to explore methods of placebo response reduction. An efficacious "drug" failed to demonstrate a significant effect compared with "placebo" (p = 0.12), although modifications either in study start time (p = 0.025) or baseline population reduction (p = 0.0028) allowed the drug to achieve a statistically significant effect compared with placebo. In epilepsy clinical trials, some seizure reduction traditionally attributed to placebo effect may reflect the natural course of the disease itself. Understanding these dynamics will allow future investigations into optimal clinical trial design and may lead to identification of more effective therapies. Ann Neurol 2015;78:329-336.

Objective Functional magnetic resonance imaging is sensitive to the variation in language network patterns. Large populations are needed to rigorously assess atypical patterns, which, even in neurological populations, are a minority.

We compared (15)O water positron emission tomography (PET) auditory and visual confrontational naming activation with an intracarotid amobarbital (Amytal) injection procedure (IAP) for language lateralization in 12 patients with intractable epilepsy. PET scans were evaluated by three raters experienced in functional imaging as well as by a region of interest (ROI) approach. Compared with IAP, raters' positive predictive value for language lateralization ranged from 88 to 91%. ROI analysis had a positive predictive value of 80%. Six patients had surgery; 1 with right-sided IAP language dominance but left-sided PET activation had dysphasia for 6 months after left temporal lobectomy.

Functional magnetic resonance imaging is sensitive to the variation in language network patterns. Large populations are needed to rigorously assess atypical patterns, which, even in neurological populations, are a minority.We studied 220 patients with focal epilepsy and 118 healthy volunteers who performed an auditory description decision task. We compared a data-driven hierarchical clustering approach to the commonly used a priori laterality index (LI) threshold (LI0.20 as atypical) to classify language patterns within frontal and temporal regions of interest. We explored (n = 128) whether IQ varied with different language activation patterns.The rate of atypical language among healthy volunteers (2.5%) and patients (24.5%) agreed with previous studies; however, we found 6 patterns of atypical language: a symmetrically bilateral, 2 unilaterally crossed, and 3 right dominant patterns. There was high agreement between classification methods, yet the cluster analysis revealed novel correlations with clinical features. Beyond the established association of left-handedness, early seizure onset, and vascular pathology with atypical language, cluster analysis identified an association of handedness with frontal lateralization, early seizure onset with temporal lateralization, and left hemisphere focus with a unilateral right pattern. Intelligence quotient was not significantly different among patterns.Language dominance is a continuum; however, our results demonstrate meaningful thresholds in classifying laterality. Atypical language patterns are less frequent but more variable than typical language patterns, posing challenges for accurate presurgical planning. Language dominance should be assessed on a regional rather than hemispheric basis, and clinical characteristics should inform evaluation of atypical language dominance. Reorganization of language is not uniformly detrimental to language functioning.

We evaluated the role of positron emission tomography (PET) with [18F]deoxyglucose (FDG) (FDG-PET) for planning surgery in 53 patients who had temporal lobectomy for uncontrolled seizures at the National Institutes of Health from 1981 to 1990. Investigators blinded to PET data used results of telemetered video-electroencephalographic ictal monitoring and other standard criteria to decide whether subdural electrodes (22 patients, i.e., the “invasive” group) should be implanted or surgery performed. PET scans were analyzed using a standard regional template. Mean lateral but not mesial temporal asymmetry was significantly higher in patients who became seizure free (p < 0.03). Patients with ≤ 15% hypometabolism were significantly more likely to be seizure free in the entire study population and the invasive subgroup. Visual identification of hypometabolism was less accurate. When a clear temporal ictal surface electroencephalographic focus was present, FDG-PET provided less additional information. FDG-PET may be particularly valuable if the surface electroencephalographic scan is nonlocalizing. In addition to helping to identify the seizure focus, it may allow limitation of invasive electrode placement to those necessary for functional mapping. When PET is used to identify epileptic foci, quantitative measurements of asymmetry should be made.

We used positron emission tomography (PET) and bolus injection of H2(15O) to measure interictal cerebral blood flow (CBF) in 32 patients who had temporal lobectomy for uncontrolled complex partial seizures. Seizure focus localization was confirmed by ictal video-electroencephalographic (video-EEG) telemetry, and patients who had imaging findings suggesting the presence of a tumor were excluded. PET-CBF studies were interpreted using a standard template by raters blinded to EEG and clinical data, and were not used in surgical planning. After surgery, patients were followed for 32 +/- 18 months. Twenty-six patients were seizure free and 6 had persistent seizures. Mean lateral temporal hypoperfusion was 8 +/- 14% in patients who became seizure free and 9 +/- 6% in patients with persistent seizures. Fourteen patients had at least 15%, and 11 at least 20% hypoperfusion, but were not more likely to be seizure free. Three additional patients had 15 to 20% hypoperfusion in the temporal lobe contralateral to their EEG focus. PET measurement of CBF using bolus H2(15O) should not be used to help select patients for temporal lobectomy.

Sedative-hypnotic antiepileptic drugs have potentially toxic effects, but their removal is often thought to be difficult and dangerous. We completely withdrew all barbiturates and benzodiazepines from 78 patients with intractable epilepsy (48 inpatients and 30 outpatients). Initially, 19 patients had plasma levels of sedative drugs above the therapeutic range; 28 were taking more than one of these drugs. Dosages of nonsedative antiepileptic drugs were adjusted to provide optimal seizure control. After 6 months of outpatient follow-up, 69 patients remained on a nonsedative regimen: 35 (51%) showed improvement in both drug toxicity and seizure control, 13 (19%) in toxicity alone, 8 (12%) in seizure control alone; 12 (16%) were unchanged, and 1 was worse. Of 9 patients restarted on sedative antiepileptic drugs by their private physicians, 4 had more toxic symptoms than at discharge, 1 had more frequent seizures, 3 were unchanged, and 1, who had had a temporal lobectomy after drug withdrawal, had less frequent seizures. Sedative drugs are not necessary for optimal seizure control, even in intractable epilepsy, and they may be safely withdrawn.

We used positron emission tomography with fluorine 18-labeled 2-deoxyglucose to study cerebral glucose metabolism in 10 patients with Lennox-Gastaut syndrome who had normal neuroradiological studies. The scans showed decreased metabolic rates relative both to those in the caudate nucleus and to normal control values in 3 patients whose seizures began before the age of 1, as well as in a patient with hyperprolinemia. No patient had a region of persistent focal hypometabolism. Metabolic rates increased in parallel with increased electroencephalographic discharges in 1 patient; 3 patients had lower metabolic rates when the electroencephalogram showed epileptiform discharges and while the patients were taking barbiturates.

Positron emission tomography with simultaneous electroencephalographic monitoring was performed with [18F]fluorodeoxyglucose in 20 patients with complex partial seizures who had normal computed tomographic scans. Seven patients had only unilateral epileptiform discharges on the electroencephalogram, 3 had predominantly unilateral discharges, and 10 had nonlocalized epileptiform abnormalities. Positron emission tomography showed a hypometabolic lesion in 16 of the 20 patients. Pathological changes in the hypometabolic region were found in postoperative specimens in 4 of 5 patients studied. Positron emission tomography was unaffected by the seizure frequency, state of alertness, or number of spike discharges during the scan. There was a tendency for patients to have higher overall metabolic rates when taking less medication. Seizures occurring during [18F]fluorodeoxyglucose uptake in 3 patients produced a hypermetabolic area at the interictal hypometabolic focus. Positron emission tomography sometimes showed more widespread hypometabolism than suspected on the basis of the scalp-recorded electroencephalogram. The frontal lobe showed a greater degree of hypometabolism than the temporal lobe in 3 patients. Focal lesions may be identified by positron emission tomography even if the electroencephalographic abnormality is not well localized.

The relationship between total and free phenytoin levels and drug toxicity was studied in 80 patients. Twenty-four were taking phenytoin alone. Drug toxicity was assessed by a "blind" rater using an eight-point standardized scoring system. The mean free phenytoin fraction was 0.076 in patients taking phenytoin alone or phenytoin and carbamazepine and 0.11 in patients taking valproic acid (p less than 0.001). The free fraction did not change with the total level over the range tested (6.7 to 39.9 micrograms/ml total phenytoin). There was a strong correlation between free and total levels (r = 0.84). Both free (r = 0.59) and total (r = 0.49) phenytoin levels were positively correlated with the toxicity score. Only total phenytoin levels showed a weak positive correlation with decreasing seizure frequency. Our results suggest that routine free phenytoin level monitoring is not necessary in most clinical situations.

We used positron emission tomography with 18F-2-deoxy-D-glucose to study the effect of carbamazepine on local cerebral metabolic rate for glucose (lCMRGlc) in 9 patients with complex partial seizures. Twenty regions of interest were evaluated. Seven control patients had serial scans without a drug change. Metabolic rates were significantly (p less than 0.05) lower in patients on carbamazepine in 6 of 20 regions of interest (3 left cerebral hemisphere, 3 right). Mean lCMRGlc was 7.4 +/- 2.0 mg/min/100 in patients on carbamazepine and 8.8 +/- 2.5 in patients off carbamazepine (p less than 0.00005; cutoff level for 180 comparisons: 0.00027). The mean (+/- SEM) difference in lCMRGlc between scans was 12 +/- 2%. No significant changes in lCMRGlc on serial scans were detected in any of the 20 regions for the control group. The mean (+/- SEM) variation for control regions of interest was 1 +/- 1%. This study showed that carbamazepine depresses cerebral glucose metabolism as much as phenytoin does, but much less than phenobarbital does. The difference in effect on lCMRGlc may be related to drug mechanisms of action, as well as to effects on memory, learning, mood, and behavior.

We studied patients with partial and primary generalized seizures using fluorine-18-labeled 2-fluorodeoxyglucose and positron emission tomography. Interictal studies of patients with partial seizures showed regions of focal or lateralized hypometabolism in 15 of 17 patients with unilateral electroencephalographic foci. Several patients had more than one hypometabolic region. In 1 patient PET ypometabolism was contralateral to the electroencephalographic epileptic focus. Six of 10 patients without definite electroencephalographic foci also showed unilateral PET hypometabolic regions. PET during complex partial seizures in 3 patients showed hypermetabolism at the site of the hypometabolic focus. A postictal scan in 1 patient showed extension of interictal temporal hypometabolism to the frontal lobe as well. Interictal scans in 8 patients with primary generalized seizures did not reveal any hypometabolic regions. One patient scanned during an attack of absence status epilepticus showed a slight decrease in metabolic rate compared to the interictal scan. Temporal lobectomy has been performed in 6 patients with focal PET hypometabolism. PET may obviate the need for depth electrode study in some patients with intractable partial seizures.

We studied the relation of plasma levels of carbamazepine (CBZ) and carbamazepine 10,11 epoxide (CBZ-E), and their ratio to drug toxicity and seizure control in 7 patients with complex partial seizures. CBZ-E/CBZ increased with increasing CBZ levels and was higher when patients were taking phenytoin or valproic acid. There were weak correlations between CBZ, CBZ-E levels, toxicity scores, and seizure control when patients were taking CBZ alone, but not when other drugs were given as well. There were no significant differences in the correlation with toxicity score or seizure frequency between CBZ, CBZ-E, or their sum. Measurement of CBZ-E levels did not provide additional information useful for monitoring clinical response to CBZ therapy.

Three young adults with intractable complex partial seizures were studied by electroencephalography, magnetoencephalography, and electrocorticography. Interictal electroencephalographic (EEG) spikes for each patient were grouped according to their morphological characteristics and distribution across channels. Mapping of simultaneously recorded magnetoencephalographic signals produced dipolar patterns from which the three-dimensional locations of equivalent current dipoles were calculated, whereas the mapping of EEG spikes showed single regions of electronegativity. The magnetic spikes were localized to the anterotemporal lobe, and the EEG spikes were localized somewhat anterior or posterior to the magnetic spikes. The magnetoencephalographic findings corresponded well with intraoperative electrocorticographic and depth-electrode findings of discharging areas located over the lateral temporal lobe and on the basal and mesial surfaces of the temporal cortex.

We observed postictal pleocytosis in 7 of 62 cerebrospinal fluid specimens obtained from 27 patients with epilepsy. Each patient had a known seizure disorder; none had any other cause for the pleocytosis. The maximum number of leukocytes was 12/mm3; the maximum number of erythrocytes was 190/mm3. Postictal pleocytosis was more common in samples obtained within 12 hours of the last seizure. Although previous studies have emphasized that pleocytosis is more common after repetitive generalized tonic-clonic seizures, we found increased leukocyte counts in cerebrospinal fluid after single simple, complex partial, or generalized tonic-clonic seizures.

We studied 21 patients with complex partial seizures during phenobarbital (PB) or primidone withdrawal. Blood levels were measured daily, and seizure frequency was monitored by nursing staff and EEG-video telemetry. Patients were monitored for one week of baseline and for five weeks after PB tapering was initiated (withdrawal). Most were observed for at least one week after levels were undetectable. When ranked seizure counts were averaged, there was a tendency for seizure rates to be highest as PB levels passed through the range 15 to 20 mg/l, compared with rates at higher or lower PB levels. There was little or no relation between the rate of PB withdrawal, other drug therapy, or initial PB level and the ratio of highest seizure frequency to mean seizure frequency. Patients withdrawing from PB may be most likely to experience an increase in seizure frequency when their PB blood level falls below 20 mg/l.