Hans Clusmann

Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex

Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K(+)-induced [Ca(2+)](i) increase in fura-2-loaded human neocortical synaptosomes (IC(50)=17 microM for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(-)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [(3)H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K(+)-induced [Ca(2+)](i) increase was prevented by the P/Q-type voltage-gated Ca(2+) channel blocker omega-agatoxin IVA. The alpha 2 delta-1, alpha 2 delta-2, and alpha 2 delta-3 subunits of voltage-gated Ca(2+) channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K(+)-evoked release of [(3)H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca(2+) channel alpha 2 delta subunit to selectively attenuate depolarization-induced Ca(2+) influx of presynaptic P/Q-type Ca(2+) channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.

Outcome of epilepsy surgery in focal cortical dysplasia

Objective: To describe the outcome of surgery in patients with drug resistant epilepsy and a histopathological diagnosis of focal cortical dysplasia. Methods and subjects: Analysis of histories and presurgical and follow up data was carried out in 53 patients with a histological diagnosis of focal cortical dysplasia. Their mean age was 24.0 years (range 5 to 46), and they included 14 children and adolescents. Mean age at seizure onset was 12.4 years (0.4 to 36) and mean seizure duration was 11.6 years (1 to 45). Results: The presurgical detection rate of focal cortical dysplasia with magnetic resonance imaging (MRI) was 96%. There were 24 temporal and 29 extratemporal resections; additional multiple subpial transections were done in 12 cases to prevent spread of seizure discharges. There was a 6% rate of complications with permanent neurological deficit, but no deaths. All resected specimens were classified by neuropathological criteria as focal cortical dysplasia. Balloon cells were seen in most cases of extratemporal focal cortical dysplasia. After a mean follow up of 50 months, 38 patients (72%) were seizure-free, two (4%) had less than two seizures a year, nine (17%) had a reduction of seizure frequency of more than 75%, and four (8%) had no improvement. Seizure outcome was similar after temporal and extratemporal surgery. The patients in need of multilobar surgery had the poorest outcome. Conclusions: Circumscribed lesionectomy of focal dysplastic lesions provides seizure relief in patients with chronic drug resistant temporal and extratemporal epilepsy. There was a trend for the best seizure outcome to be in patients with early presurgical evaluation and early surgery, and in whom lesions were identified on the preoperative MRI studies.

Characteristics and Surgical Outcomes of Patients With Refractory Magnetic Resonance Imaging–Negative Epilepsies

OBJECTIVE To explore several characteristics of patients with pharmacoresistant epilepsy without distinct lesions on magnetic resonance images (MRI(-)), who account for a relevant proportion of presurgical patient cohorts. DESIGN Retrospective case series. SETTING University epilepsy center. PATIENTS A cohort of 1200 patients who had comprehensive presurgical assessment from January 1, 2000, through December 31, 2006. MAIN OUTCOME MEASURES Frequency of MRI(-) patients in the total presurgical cohort, seizure-free outcome rates in patients who had surgery and those who did not, outcome predictors, and spatial properties of epileptogenic areas in MRI(-) patients with epilepsy. All MRI(-) patients were retrospectively analyzed. Presurgical MRIs were reevaluated for subtle cortical dysplasias by postprocessing and visual reassessment. RESULTS One-hundred ninety MRI(-) patients were identified (16% of all presurgical candidates); 29 (15%) had surgery. Eleven (38%) became seizure free (including those with auras only; 45%). Surgical therapy was more frequently offered to MRI(+) patients (76%; P < .001), and their outcome was also superior (66% seizure-free; P = .001). The seizure-free rate of 16% in MRI(-) patients who did not have surgery was, however, inferior to that of the MRI(-) patients who did (P = .008). Nine MRI(-) patients who had surgery had distinct histopathological lesions, 8 of which turned out to be retrospectively detectable on presurgical MRI. Seven of the MRI(-) but histopathologically lesional patients became seizure free compared with only 4 of 20 patients without histopathological lesions (P = .003). Three-fifths of the histopathologically nonlesional patients had multifocal or extensive epileptogenic areas. CONCLUSIONS Patients with epilepsy who are MRI(-) can be successfully treated with surgery. Improved sensitivity of MRI will improve the outcomes of presurgically studied patients. Surgical failures in patients without histopathological lesions mostly result from extensive epileptogenic areas.

Analysis of different types of resection for pediatric patients with temporal lobe epilepsy.

OBJECTIVEResection strategies for the treatment of temporal lobe epilepsy (TLE) are a matter of discussion. Few data on the significance of resection type are available for pediatric patients with TLE. METHODSData for a series of 89 children who were surgically treated for TLE were analyzed. A first cohort of patients were mainly surgically treated with anterior temporal lobectomies. For a second cohort, resections were preoperatively “tailored” to the lesion and presumed epileptogenic area. RESULTSThe follow-up period was 46 months (range, 14–118 mo). Seventy-seven patients (87%) attained satisfactory seizure control (82% Engel Class I and 5% Class II). For 12 patients (13%), seizure control was unsatisfactory (8% Class III and 5% Class IV). Anterior temporal lobectomies resulted in 94% satisfactory seizure control (33 patients), whereas the success rates were only 74% (20 patients) for amygdalohippocampectomy (AH) (P = 0.023) and 77% (13 patients) for lesionectomy plus hippocampectomy (not significant). All patients who underwent purely lateral temporal lesionectomies became seizure-free (14 patients). Logistic regression revealed the factors of AH (P = 0.021) and left-side surgery (P = 0.017) as significant predictors of unsatisfactory seizure control. Satisfactory seizure control was not dependent on the histopathological diagnoses. There was a low rate of verbal memory deterioration after left-side operations. Neuropsychological deterioration was rare after right temporal resections. Attentional and contralateral functions improved after surgery. CONCLUSIONSurgery for the treatment of juvenile TLE is successful and safe, but the resection type may influence outcomes. Results after AHs were disappointing, probably because of difficulties in precise localization of the epileptogenic focus among children. Neuropsychological results demonstrated minimal rates of deterioration and significant improvements in contralateral functions. Surgical treatment of juvenile TLE should be encouraged, but the use of especially left AH should possibly be restricted.

Transsylvian keyhole functional hemispherectomy.

OBJECTIVETo describe the technical steps, advantages, and limitations of a quicker, minimal-exposure, functional hemispherectomy procedure developed from a hemispherical deafferentation technique previously described. METHODSThe surgical approach using the transsylvian/transsulcal passage to the ventricular system, with the anatomic orientation points and key features for planning of the small trepanation, is described. Through a linear incision, a craniotomy (4 × 4 to 4 × 5 cm) is placed over the sylvian fissure. Transsylvian exposure of the circular sulcus allows transcortical exposure of the entire ventricular system, from the frontal horn to the temporal horn encircling the insular cortex. The frontobasal and mesial white matter is disconnected via the intraventricular approach, with a callosotomy. An amygdalohippocampectomy completes the dissection. The experience with 20 patients who were treated using the transsylvian keyhole hemispherectomy technique is summarized. RESULTSThe operation time was significantly shorter (mean, 3.6 h) than with the Rasmussen technique (mean, 6.3 h) and 25% shorter than with the transcortical perisylvian technique (mean, 4.9 h). The proportion of patients requiring blood replacements was lower (15 versus 58%), as was the mean amount of transfused blood. The mean follow-up period was 46 months; 88% of patients were in Engel Outcome Class I, 6% in Class III, and 6% in Class IV. CONCLUSIONThe transsylvian keyhole procedure has been demonstrated to further reduce operation time and the need for blood replacement. It is most easily performed in cases with enlarged ventricles or perinatal ischemic cysts and is not recommended for hemimegalencephaly. The immediate seizure relief was satisfying. This minimal-exposure approach seems to be a satisfying alternative among possible functional hemispherectomy procedures.

Neuropsychological Outcome after Selective Amygdalohippocampectomy with Transsylvian versus Transcortical Approach: A Randomized Prospective Clinical Trial of Surgery for Temporal Lobe Epilepsy

Summary:  Purpose: Selective amygdalohippocampectomy (SAH) is a surgical treatment option for patients with medically intractable mesial temporal lobe epilepsy. In contrast to standard anterior temporal lobectomy, resection of unaffected tissue is limited, although it achieves equal seizure outcomes in selected patients. In SAH, the mesial structures can be approached by different routes, the transsylvian approach and the transcortical approach. Advantages or disadvantages with respect to postoperative cognitive outcome are still a matter of debate.

Pre- and postoperative verbal memory in pediatric patients with temporal lobe epilepsy

Outcome studies concerning memory after pediatric temporal lobe surgery in the treatment of epilepsy are rare and have not yielded consistent results. In the present study, 55 children and adolescents with temporal lobe epilepsy (TLE; 26 left, 29 right, 6-17 years) performed a verbal memory test before and 3 as well as 12 months after different types of temporal lobe resections (anterior lobectomy, amygdalo-hippocampectomy (AH), lesionectomy (LX)). Groups did not significantly differ before surgery. Three months after surgery, the left resected group showed a decline in learning and delayed recall, and performed significantly lower than the right resected group. Recoveries were evident 1 year after surgery. The postoperative memory declines were associated with a left-sided resection and a higher preoperative performance. Comparisons on the different resection types suggest a special risk in patients undergoing a left-sided AH. In summary, our results indicate a functional association of verbal memory functions with the left temporal lobe similar to findings in adult patients. Declines after left-sided temporal resections seem to be reversible at least for part of the children, perhaps due to the greater plasticity of the immature brain.

Androgen receptor mRNA expression in the human hippocampus.

The androgen receptor (AR) plays a central role in mediating androgen action. Since the hippocampus is a target of steroid modulation, we studied the expression of AR mRNAs in hippocampal tissue specimens from patients undergoing epilepsy surgery (n=42). AR mRNA expression was in the same order of magnitude than in prostate tissue, known for its high expression of AR. AR mRNA concentrations showed no significant difference in AR mRNA expression between men (49.3+/-8.0 arbitrary units (aU); mean+/-SEM) and women (54.3+/-11.2 aU) and no sex-specific hippocampal lateralization pattern was observed. No relationship could be detected between duration of epilepsy, individual seizure frequency, age of the patients and the expression levels of AR. The high expression of AR in the hippocampus suggests that this human brain area is an important target for androgen action.

Surgical Treatment for Refractory Temporal Lobe Epilepsy in the Elderly: Seizure Outcome and Neuropsychological Sequels Compared with a Younger Cohort

Summary:  Purpose: Surgical treatment of refractory temporal lobe epilepsy (TLE) is promising for selected patients, but only little experience has been acquired in operating on older patients, especially with limited resections. We intend to delineate clinical and surgical factors influencing outcome in patients older than 50 years at operation and to compare the results with those of a younger patient cohort.

Risks and benefits of invasive epilepsy surgery workup with implanted subdural and depth electrodes.

Purpose:  In patients with pharmacoresistant focal‐onset seizures, invasive presurgical workup can identify epilepsy surgery options when noninvasive workup has failed. Yet, the potential benefit must be balanced with procedure‐related risks. This study examines risks associated with the implantation of subdural strip and grid, and intracerebral depth electrodes. Benefit of invasive monitoring is measured by seizure outcomes. Diagnostic procedures made possible by electrode implantation are described.