Kenneth D. Laxer

Spatio-temporal correlations in human gamma band electrocorticograms.

Animal electrocorticogram (ECoG) studies have shown that spatial patterns in the gamma band (>20 Hz) reflect perceptual categorization. Spatio-temporal correlations were investigated in the 20-50 Hz range in search for similar phenomena in human ECoG. ECoGs were recorded in a somatosensory discrimination task from 64-electrode subdural grid arrays, with inter-electrode spacing of 1 cm, overlying somatosensory, motor and superior temporal cortices in 2 patients with intractable epilepsy. Bootstrap techniques were devised to analyze the spatial and temporal characteristics of the correlations. Despite an extensive search, no evidence was found for globally correlated activity related to behavior either in narrow (1.e., 35-45 Hz) or broad (i.e., 20-50 Hz) bands. Spatial patterns, extracted using principal component analysis, could not be classified with respect to stimulus type in any time interval. Instead, spatially and temporally intermittent synchronization was observed between pairs of electrodes in 1 cm X 1 cm regions with high variability within and across trials. The distribution of correlation coefficients differed substantially from background levels at inter-electrode distances of 1 cm and 1.4 cm but not 2 cm or more. The minimum duration of correlation, the decorrelation time, of the ECoG was about 50 msec; the average correlation duration at 1 cm inter-electrode distance was about 150 msec; and the recurrence rate of significant correlation peaks was about 1.3/sec. The findings suggest that the surface diameters of domains of spatially correlated activity underlying perceptual categorization in human gamma band ECoG are limited to less than 2 cm and that the intermittent synchronization observed across separations of 1 cm and 1.4 cm is not solely due to volume conduction. Thus, if such gamma band spatial patterns exist in the human brain, no existing technology would be capable of measuring them at the scalp, and subdural electrode arrays for cortical surface recording would have to have spacings under 5 mm.

Felbamate A double‐blind controlled trial in patients undergoing presurgical evaluation of partial seizures

We studied the efficacy and safety of felbamate, an investigational antiepileptic drug, in a unique, double-blind, placebo-controlled trial. Sixty-four patients with refractory partial-onset seizures who completed a routine evaluation for epilepsy surgery met seizure frequency entry criteria. Each patient received felbamate or placebo in addition to the anticonvulsant regimen present at the conclusion of the presurgical evaluation. The treatment phase consisted of an 8-day inpatient period and a 21-day outpatient period. The efficacy variable was time to fourth seizure. The difference in time to fourth seizure was statistically significant (p = 0.028) in favor of felbamate. Eighty-eight percent of the patients in the placebo group had a fourth seizure during the treatment phase compared with 46% of the patients in the felbamate group (p = 0.001). Adverse experiences with felbamate were generally mild or moderate in severity. This trial demonstrated the ability of felbamate to quickly and safely reduce the occurrence of frequent partial-onset seizures and maintain effective seizure control following reductions in the dosages of standard antiepileptic drugs.

A multicenter, prospective pilot study of gamma knife radiosurgery for mesial temporal lobe epilepsy: Seizure response, adverse events, and verbal memory

The safety, efficacy, and morbidity of radiosurgery (RS) must be established before it can be offered as an alternative to open surgery for unilateral mesial temporal lobe epilepsy. We report the 3‐year outcomes of a multicenter, prospective pilot study of RS.

Voxel-based optimized morphometry (VBM) of gray and white matter in temporal lobe epilepsy (TLE) with and without mesial temporal sclerosis.

Summary:  Purpose: In temporal lobe epilepsy (TLE) with evidence of hippocampal sclerosis (TLE‐MTS) volumetric gray (GM) and white (WM) matter abnormalities are not restricted to the hippocampus but also are found in extrahippocampal structures. Less is known about extrahippocampal volumetric abnormalities in TLE without hippocampal sclerosis (TLE‐no). In this study, we used optimized voxel‐based morphometry (VBM) with and without modulation with the following aims: (a) to identify WM and GM abnormalities beyond the hippocampus in TLE‐MTS and TLE‐no; and (b) to determine whether extratemporal WM and GM abnormalities differ between TLE‐MTS and TLE‐no.

Oxcarbazepine Double-blind, randomized, placebo-control, monotherapy trial for partial seizures

Objective: To evaluate the efficacy and safety of oxcarbazepine in a placebo-control trial. Methods: A multicenter, double-blind, randomized, placebo-control, two-arm parallel group, monotherapy design was used to compare oxcarbazepine administered 1,200 mg twice daily to placebo in hospitalized patients with refractory partial seizures, including simple and complex partial seizures and partial seizures evolving to secondarily generalized seizures. Patients exited the trial after completing the 10-day double-blind treatment phase or after experiencing four partial seizures, two new-onset secondarily generalized seizures, serial seizures, or status epilepticus, whichever came first. Results: Analysis of the primary efficacy variable—time to meeting one of the exit criteria—showed a statistically significant effect in favor of oxcarbazepine (p = 0.0001). The secondary efficacy variables—percentage of patients who met one of the exit criteria (p = 0.0001) and total partial seizure frequency per 9 days during the double-blind treatment (p = 0.0001)—were also statistically significant in favor of oxcarbazepine. Conclusion: These results demonstrate that oxcarbazepine given as monotherapy is effective and safe for the treatment of partial seizures in this paradigm.OBJECTIVE To evaluate the efficacy and safety of oxcarbazepine in a placebo-control trial. METHODS A multicenter, double-blind, randomized, placebo-control, two-arm parallel group, monotherapy design was used to compare oxcarbazepine administered 1,200 mg twice daily to placebo in hospitalized patients with refractory partial seizures, including simple and complex partial seizures and partial seizures evolving to secondarily generalized seizures. Patients exited the trial after completing the 10-day double-blind treatment phase or after experiencing four partial seizures, two new-onset secondarily generalized seizures, serial seizures, or status epilepticus, whichever came first. RESULTS Analysis of the primary efficacy variable--time to meeting one of the exit criteria--showed a statistically significant effect in favor of oxcarbazepine (p = 0.0001). The secondary efficacy variables--percentage of patients who met one of the exit criteria (p = 0.0001) and total partial seizure frequency per 9 days during the double-blind treatment (p = 0.0001)--were also statistically significant in favor of oxcarbazepine. CONCLUSION These results demonstrate that oxcarbazepine given as monotherapy is effective and safe for the treatment of partial seizures in this paradigm.

Semiology of temporal lobe seizures: value in lateralizing the seizure focus.

Summary: Purpose: To determine the lateralizing value of the clinical manifestations of seizures in patients with temporal lobe epilepsy (TLE), we made a retrospective videotape analysis of complex partial seizures (CPS) in 55 patients who underwent temporal lobectomy and were seizure‐free postopera‐tively for >2 years.

Prognostic Value of Qualitative Magnetic Resonance Imaging Hippocampal Abnormalities in Patients Undergoing Temporal Lobectomy for Medically Refractory Seizures

Summary: In patients with temporal lobe epilepsy (TLE), high‐resolution, magnetic resonance imaging (MRI) frequently demonstrates hippocampal atrophy and increased hippocampal signal. To assess the prognostic value of these findings, we studied 51 patients evaluated prospectively by a radiologist blinded to other preoperative evaluations. Thirty‐one of 51 (61%) patients undergoing temporal lobectomy had visually apparent hippocampal atrophy o r increased hippocampal signal on MRI (25 ipsilateral 3 contralateral, and bilateral to the operated site). Patients with ipsilateral abnormalities became seizure‐free more frequently than patients with normal scans [24 of 25 (96%) vs. 10 of 20 (50%) p < 0.015]. Both ipsilateral hippocampal atrophy and ipsilateral increased hippocampal signal independently predicted a seizure‐free outcome. Qualitative MRI provides important prognostic information in patients undergoing temporal lobectomy.

Widespread Neocortical Abnormalities in Temporal Lobe Epilepsy With And Without Mesial Sclerosis

PURPOSE Extrafocal structural abnormalities have been consistently described in temporal lobe epilepsy (TLE) with mesial temporal lobe sclerosis (TLE-MTS). In TLE without MTS (TLE-no) extrafocal abnormalities are more subtle and often require region of interest analyses for their detection. Cortical thickness measurements might be better suited to detect such subtle abnormalities than conventional whole brain volumetric techniques which are often negative in TLE-no. The aim of this study was to seek and characterize patterns of cortical thinning in TLE-MTS and TLE-no. METHODS T1 weighted whole brain images were acquired on a 4 T magnet in 66 subjects (35 controls, 15 TLE-MTS, 16 TLE-no). Cortical thickness measurements were obtained using the FreeSurfer software routine. Group comparisons and correlation analyses were done using the statistical routine of FreeSurfer (FDR, p=0.05). RESULTS TLE-MTS and TLE-no showed both widespread temporal and extratemporal cortical thinning. In TLE-MTS, the inferior medial and posterior temporal regions were most prominently affected while lateral temporal and opercular regions were more affected in TLE-no. The correlation analysis showed a significant correlation between the ipsilateral hippocampal volume and regions of thinning in TLE-MTS and between inferior temporal cortical thickness and thinning in extratemporal cortical regions in TLE-no. CONCLUSION The pattern of thinning in TLE-no was different from the pattern in TLE-MTS. This finding suggests that different epileptogenic networks could be involved in TLE-MTS and TLE and further supports the hypothesis that TLE-MTS and TLE-no might represent two distinct TLE syndromes.

Lateralization of human focal epilepsy by 31P magnetic resonance spectroscopic imaging

We attempted to lateralize the epileptogenic focus (seven temporal lobe hippocampal foci, one frontal lobe focus) in medically refractory unilateral complex partial seizures, using noninvasive 31P magnetic resonance spectroscopic imaging (MRSI) blindly and interictally to compare hippocampal or frontal regions. The seizure foci were more alkaline (intracellular pH = 7.17 ± 0.03) compared with the contralateral region (7.06 ± 0.02, p < 0.01) in all eight cases; the inorganic phosphate was relatively increased (240 ± 50% of contralateral, seven of eight cases, p < 0.01); and phosphomonoesters were relatively reduced (68 ± 9% of contralateral, seven of eight cases, p < 0.01). Other phosphorus metabolites were symmetric (± 10%). 31P MRSI correctly lateralized the seizure focus in all eight cases. By comparison, imaging correctly lateralized four cases and SPECT, two cases. In conclusion, 31P MRSI is a useful tool for the noninvasive clinical assessment of focal epilepsy and can accurately lateralize the epileptogenic focus.

Assessment of Ganaxolone's Anticonvulsant Activity Using a Randomized, Double‐Blind, Presurgical Trial Design

Summary: Purpose: A double‐blind, randomized, placebo‐controlled clinical trial to examine the safety, tolerability, and antiepileptic activity of ganaxolone in patients after withdrawal from other antiepileptic drugs during presurgical evaluations was performed.