Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy.

OBJECTIVE: To evaluate the efficacy and safety of ezogabine (United States adopted name)/retigabine (international nonproprietary name) (EZG[RTG]) 1,200 mg/day as adjunctive treatment in adults with drug-resistant epilepsy with partial-onset seizures with or without secondary generalization. METHODS: RESTORE 1 was a multicenter, randomized, double-blind, parallel-group trial. Following a prospective 8-week baseline phase, patients entered an 18-week double-blind treatment period (6-week forced dose titration to EZG[RTG] 1,200 mg/day in 3 equally divided doses or placebo, followed by a 12-week maintenance phase). Results were analyzed on an intent-to-treat basis for the entire 18-week period and for patients reaching the maintenance phase. RESULTS: In 306 patients randomized, 305 received EZG(RTG) 1,200 mg/day (n = 153) or placebo (n = 152). Median percent reduction in total partial-seizure frequency was 44.3% vs 17.5% (p < 0.001) for EZG(RTG) and placebo, respectively, during the 18-week double-blind period; responder rates (≥50% reduction in total partial-seizure frequency from baseline) were 44.4% vs 17.8% (p < 0.001). In 256 patients (EZG[RTG], 119; placebo, 137) entering the 12-week maintenance phase, median percent reduction in seizure frequency for EZG(RTG) vs placebo was 54.5% and 18.9% (p < 0.001), respectively; responder rates were 55.5% vs 22.6% (p < 0.001). The proportion of patients discontinuing due to treatment-emergent adverse events (TEAEs) was 26.8% (EZG[RTG]) vs 8.6% (placebo). Dizziness, somnolence, fatigue, confusion, dysarthria, urinary tract infection, ataxia, and blurred vision were the most common TEAEs reported by more patients treated with EZG(RTG) than placebo. CONCLUSIONS: This study demonstrates that EZG(RTG) is effective as add-on therapy for reducing seizure frequency in patients with drug-resistant partial-onset seizures. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that EZG(RTG) 1,200 mg/day is effective as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization.

Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy.

OBJECTIVE: To assess the efficacy and tolerability of adjunctive levetiracetam in patients with uncontrolled generalized tonic-clonic (GTC) seizures associated with idiopathic generalized epilepsies (IGE). METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled adults and children (4 to 65 years) with IGE experiencing >or=3 GTC seizures during the 8-week baseline period (4-week retrospective and 4-week prospective), despite receiving stable doses of one or two antiepileptic drugs (AEDs). Patients were randomized to levetiracetam (target dose 3,000 mg/day for adults; 60 mg/kg/day for children) or placebo and a 4-week titration period was followed by a 20-week evaluation period. RESULTS: Of 229 patients screened, 164 were randomized (levetiracetam, n = 80; placebo, n = 84). Levetiracetam produced a greater mean reduction in GTC seizure frequency per week over the treatment period (56.5%) than placebo (28.2%; p = 0.004). The percentage of patients who had >or=50% reduction of GTC seizure frequency per week (responders) during the treatment period was 72.2% for levetiracetam and 45.2% for placebo (p < 0.001; OR 3.28; 95% CI 1.68 to 6.38). During the first 2-week treatment 64.6% of patients on levetiracetam and 45.2% on placebo (p = 0.018) were classified as responders. During the evaluation period the percent of patients free of GTC seizures (34.2% vs 10.7%; p < 0.001) and all seizure types (24.1% vs 8.3%; p = 0.009) was greater for levetiracetam than placebo. Levetiracetam was well tolerated with 1.3% of patients discontinuing therapy due to adverse events vs 4.8% on placebo. CONCLUSION: Adjunctive levetiracetam is an effective and well-tolerated antiepileptic drug for treating generalized tonic-clonic seizures in patients with idiopathic generalized epilepsies.

SPECT brain imaging in epilepsy: a meta-analysis.

UNLABELLED: A meta-analysis of SPECT brain imaging in epilepsy was performed to derive the sensitivity and specificity of interictal, postictal or ictal rCBF patterns to identify a seizure focus in medically refractory patients. METHODS: Papers were obtained by pooling all published articles identified by two independent literature searches: (a) Dialnet (EMBASE) or Radline by CD-ROM and (b) Current Contents searched manually. Literature inclusion criteria were: (a) patients had a localization-related epileptic syndrome; (b) more than six patients were reported; and (c) patients had at least an interictal EEG-documented epileptiform abnormality. Of 46 papers meeting these criteria, 30 contained extractable data. SPECT results were compared to localization by standard diagnostic evaluation and surgical outcome. Meta-analytic sensitivities for SPECT localization in patients with temporal lobe seizures relative to diagnostic evaluation were 0.44 (interictal), 0.75 (postictal) and 0.97 (ictal). Similar results were obtained relative to surgical outcome. False-positive rates were low relative to diagnostic evaluation (7.4% for interictal and 1.5% for postictal studies) and surgical outcome (4.4% for interictal and 0.0% for postictal studies). RESULTS: The results were not dependent on tracer used (or dose), the presence of CT-identified structural abnormalities, blinding of image interpretation or camera quality (although data were more variable with low-resolution cameras). There were insufficient data for conclusions regarding extratemporal-seizure or pediatric epilepsy populations. CONCLUSION: Insights gained from reviewing this literature yielded recommendations for minimal information that should be provided in future reports. Additional recommendations regarding the nature and focus of future studies also are provided. The most important of these is that institutions using SPECT imaging in epilepsy should perform ictal, preferably, or postictal scanning in combination with interictal scanning.

Tiagabine therapy for complex partial seizures. A dose-frequency study. The Tiagabine Study Group.

OBJECTIVE: To evaluate the efficacy and safety of 2 regimens of tiagabine as add-on therapy for patients with complex partial seizures (CPSs) that are refractory to other treatment. DESIGN: Randomized, double-blind, placebo-controlled, add-on, parallel-group trial with an 8-week baseline period, 12-week experimental period (4 weeks of dose titration and 8 weeks of fixed-dose therapy), and 4-week termination period. SETTING: Twenty-six centers throughout the United States. PATIENTS: Three hundred fifty-one patients were enrolled, 318 were entered in the double-blind period, and 271 completed the study. INTERVENTIONS: Tiagabine, 16 mg 2 times per day (106 patients); tiagabine, 8 mg 4 times daily (105 patients); and placebo (107 patients). The doses of tiagabine were titrated in 3 steps to the fixed dose. MAIN OUTCOME MEASURE: The median change in the 4-week rate of CPSs from baseline to experimental period. RESULTS: The median change from baseline was -1.6 CPSs per 4 weeks in the group of patients who were given tiagabine 2 times per day, and it was -1.2 CPSs in the group of patients who were given tiagabine 4 time per day (P = .06 and P = .02, respectively, compared with placebo). The 4-week seizure frequency was reduced by 50% or more in 31% of the patients who were given tiagabine 2 times per day and in 27% of the patients who were given tiagabine 4 times per day vs 10% of the placebo-treated patients (P < or = .001 for each tiagabine-treated group compared with the placebo group). The most frequent adverse events involved the central nervous system and occurred in comparable proportions in the 3 treatment groups. Similar proportions of patients discontinued the study prematurely for adverse events. CONCLUSIONS: Tiagabine administered 2 and 4 times daily as add-on pharmacotherapy was effective in reducing CPSs in patients with epilepsy whose conditions were refractory to treatment with other antiepileptic agents, and it was well tolerated.

Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, cross-over trial.

The efficacy and safety of lamotrigine (LTG), a new antiepileptic drug (AED), were evaluated in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 98 patients with refractory partial seizures. Each treatment period lasted 14 weeks. Most patients were titrated to a LTG maintenance dose of 400 mg/day. Seizure frequency with LTG decreased by > or = 50%, as compared with placebo, in one fifth of patients. Overall median seizure frequency decreased by 25% with LTG as compared with placebo (p < 0.001). With LTG, the number of seizure days decreased by 18% as compared with placebo (p < 0.01), and investigator global evaluation of overall patient clinical status favored LTG by 2:1 (p = 0.013). Plasma LTG concentrations appeared to be linearly related to dosage. LTG had no clinically important effects on the plasma concentrations of concomitant AEDs. Adverse experiences were generally minor and most frequently were CNS-related (e.g., ataxia, dizziness, diplopia, headache). Most were transient and resolved without discontinuing treatment. Five patients withdrew as a result of adverse experiences while receiving LTG, including 3 patients with rash. One placebo patient was also withdrawn because of rash. The addition of twice-daily LTG to an existing AED regimen was safe, effective, and well tolerated in these medically refractory partial seizure patients.

Comparison of technetium-99m-ECD to Xenon-133 SPECT in normal controls and in patients with mild to moderate regional cerebral blood flow abnormalities.

Technetium-99m-1,1-ethyl cysteinate dimer (ECD) has been proposed as a "chemical microsphere" for SPECT measurement of regional cerebral blood flow (rCBF). However, its distribution has not yet been compared in humans to an established rCBF measure. Therefore, we compared the uptake and distribution of ECD with rCBF measured by 133Xe SPECT in subjects with mild to moderate flow abnormalities and in normal volunteers. Blood and urine chemistries and vital signs were unchanged from pre-ECD values up to seven days postinjection. Profile plots demonstrated pattern agreement between rCBF ratios (133Xe) and ECD count density ratios. A significant correlation of rCBF ratios to ECD count density ratios was observed (r = 0.77), with a slope of 0.64 and intercept of 0.36. To explore whether or not the relationship between rCBF and ECD was dependent on absolute flow, ECD region of interest data were expressed in units of ml/min/100 g by equating global CBF (133Xe) and ECD global count density. A closer correlation (r = 0.88) was found for these data than for the count ratio data. The slope was closer to one (m = 0.83) and the intercept was closer to zero (b = 8.2). Also, a significant correlation was observed between ECD-derived rCBF and 133Xe rCBF in the lesion area (r = 0.92) for patients with well-demarcated rCBF lesions. The slope (0.80) suggested a slight underestimation of lesion flow by ECD. Finally, ECD clearance from cortical gray matter ROIs derived from high-resolution scans from 1 to 4 hr postinjection was slow (2.4%/hr). In summary, ECD is a safe and effective marker of regional cerebral perfusion. The distribution of ECD is linearly related to rCBF measured by 133Xe SPECT, although our data suggest a mild underestimation of flow at the high end of the normal range.

Reassessment of the clinical significance of periodic lateralized epileptiform discharges in pediatric patients.

A review of clinical data from 18 pediatric patients with periodic lateralized epileptiform discharges and bilateral independent periodic lateralized epileptiform discharges (PLEDs and BIPLEDs) showed 2 with chronic neurologic illness, 6 with a history of prior seizures, 14 with depressed sensorium at the time of EEG, 5 deaths, and 8 of 13 survivors with neurologic deficits. These findings are similar to the combined data from reports involving adult patients only. Separating pediatric patients with PLEDs from those with BIPLEDs shows some influence from patients with BIPLEDs. Overall, our data do not suggest significant clinical differences for PLEDs between children and adults.

Defining the role of structural lesions and metabolic abnormalities in periodic lateralized epileptiform discharges.

We reviewed the EEG, clinical manifestations, computed tomography (CT) and magnetic resonance imaging (MRI) scans of 39 patients with periodic lateralized epileptiform discharges (PLEDs) or bilateral periodic lateralized epileptiform discharges (BIPLEDs) to determine the role of structural lesions (SL) and metabolic abnormalities (MA) in their pathogenesis. Thirty-eight patients had CT and 7 had MRI scans. Thirty-eight had lesions on CT or MRI. All those with PLEDs consistently had lesions on the side of the discharges, and 5 of 6 with BIPLEDs had lesions on both hemispheres. A subgroup of 23 patients with metabolic determination within 24 h of EEG all showed mild to moderate MA. They all also had SL. These findings support a primary role for SL but cannot exclude an additional role for MA.

Single photon emission computed tomography in epilepsy.

Functional brain imaging by either single photon emission computed tomography (SPECT) or positron emission tomography (PET) is now a well-established technique in the diagnosis and evaluation of the epilepsies. Perhaps only in stroke have these emerging technologies proven of greater significance. Scalp, cortical, or depth electroencephalographic (EEG) data previously have been the gold standards for the localization and subcharacterization of epileptic activity in the human brain. Yet, they are fraught with difficult interpretations, technical difficulties, and limitations in sampling accuracy. Both SPECT and PET have localizing power approaching that of combined scalp and depth EEG. In the following discussion, a brief overview of the results of PET investigations in epilepsy is presented as background and comparative material for the concurrent and, more recently, dominant role of SPECT in evaluating patients with seizure activity. SPECT results in the interictal state in partial and generalized seizure activity are reviewed followed by an analysis of the role of ictal SPECT imaging in epilepsy. Next, relationships among interictal hypoperfusion (or hypometabolism) and computed tomography, magnetic resonance imaging, neuropathology, clinical severity, and cognitive function are discussed. The role of perfusion or metabolism imaging in the management of antiepileptic pharmacotherapy is also discussed, and the potential for receptor imaging in the evaluation of the epilepsies is examined. Finally, application in pediatric epilepsy are presented.

Delayed contralateral hemiplegia following herpes zoster ophthalmicus: should antiviral therapy be used?

We review clinical virological studies in the syndrome of delayed contralateral hemiplegia following herpes zoster ophthalmicus. Virus could not be isolated from the cerebrospinal fluid (CSF) of the present case, nor was antiviral antibody found in the CSF. There appear to have been no reports of successful virus isolation from the CSF although there are reports of antibody in the spinal fluid. Thus the evidence for ongoing viral replication in the central nervous system is marginal. It is suggested that the sensitive antibody assay against membrane antigens (FAMA) be used in the future as a guide to antiviral therapy.

Evaluation of ambulatory cassette EEG monitoring: III. Diagnostic accuracy compared to intensive inpatient EEG monitoring.

We assessed the ability to recognize epileptiform abnormalities on a video review of ambulatory cassette EEGs (A/EEG) by comparing two independent interpretations of an A/EEG to those derived from a routine recording and intensive monitoring by cable telemetry (C/EEG) of the same 40 patients. Both A/EEG readings concurred with the C/EEG interpretation as to normality or epileptiform abnormality in 77% of cases. Seventy-nine percent of focal and 100% of generalized interictal abnormalities, as well as all seizures, noted on C/EEG were detected by both A/EEG reviewers. Of patients with normal baseline EEGs, 37% showed epileptiform features on A/EEG versus 44% with C/EEG. Limits to the characterization of abnormalities by A/EEG and a protocol for the video review of A/EEG tapes are discussed. In those specific areas for which intensive surface EEG monitoring is most useful, ambulatory cassette EEG appears to be an acceptable intermediate-level alternative.

An evaluation of ambulatory, cassette EEG monitoring: I. Montage design.

Ambulatory EEGs using cassette tape recorders have only four channels. Questions have been raised about the limitations this imposes on detection of focal interictal epileptiform events. A review of EEGs from inpatients undergoing prolonged monitoring demonstrated an overwhelming representation of these abnormalities in the frontal and anterior temporal scalp regions. Three-channel montages were designed to sample these regions and were tested by simultaneously recording them with multichannel montages. Successful montages combining a frontal transverse and two longitudinal channels adequately detected 74 to 100% of interictal epileptic events.

An evaluation of ambulatory, cassette EEG monitoring: II. Detection of interictal abnormalities.

Although they are clearly useful for generalized ictal events, the ability of ambulatory, cassette EEG systems to detect interictal abnormalities routinely remains in question. The EEGs of 25 patients have been simultaneously monitored by cable telemetry and Oxford Medilog recorder, using a three-channel montage. Output from the cassette recorder amplifiers was of high fidelity compared to cable telemetry, and EEG reproduction from tape suffered only minimal signal degradation. Ambulatory EEG detection rate for interictal abnormalities averaged 85% and was commensurate with the montage design study. Perceptual demand during video scanning, including the recognition of normal transients and artifacts, was addressed as an important limiting factor. Ambulatory EEG monitoring by cassette recorder appears to be a useful intermediate-level screening technique for epileptiform abnormalities, both ictal and interictal.

Orientation detectors in the primary somatosensory neocortex of the raccoon.

An analysis of response properties of single neurons in the forepaw region of the primary somatosensory neocortex (SI) of the raccoon was undertaken to gain a better understanding of the neural bases of tactile form discrimination. In the course of this investigation a new type of feature detector neuron which responded preferentially to tactile stimulus orientation was discovered. Within a sample of 110 neurons responding to light touch, two categories of cells were noted in terms of the type of stimulation best able to excite them. One category (linear units) was preferentially responsive to indentations of the skin using a narrow elongated stimulus probe applied in a particular orientation. The other category (round field units) gave a maximum response to stimulation with a round stimulus probe applied anywhere within a roughly circular receptive field. The response pattern of some SI neurons to a maintained indentation of the skin consisted of early and late excitatory responses, separated by a depression in responding. The second excitatory response appeared to be more influenced by variations in stimulus parameters than was the first.