Therapeutic Drug Monitoring of 6 New-Generation Antiseizure Medications Using a Mass Spectrometry Method: Analysis of 2-Year Experience in a Large Cohort of Korean Epilepsy Patients.

CONTEXT.­: New-generation antiseizure medications (ASMs) are increasingly prescribed, and therapeutic drug monitoring (TDM) has been proposed to improve clinical outcome. However, clinical TDM data on new-generation ASMs are scarce. OBJECTIVE.­: To develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for therapeutic drug monitoring (TDM) of 6 new-generation ASMs in serum and analyze the clinical TDM data from a large cohort of Korean patients with epilepsy. DESIGN.­: Stable isotope-labeled internal standards were added to protein precipitations of serum. One microliter of sample was separated on Agilent Poroshell EC-C18 column, and lacosamide, perampanel, gabapentin, pregabalin, vigabatrin, and rufinamide were simultaneously quantified by Agilent 6460 triple-quad mass spectrometer in multiple-reaction monitoring mode. Linearity, sensitivity, precision, accuracy, specificity, carryover, extraction recovery, and matrix effect were evaluated. TDM data of 458 samples from 363 Korean epilepsy patients were analyzed. RESULTS.­: The method was linear with limit of detection less than 0.05 µg/mL in all analytes. Intraassay and interassay imprecisions were less than 5% coefficient of variation. Accuracy was within ±15% bias. Extraction recovery ranged from 85.9% to 98.8%. A total of 88% (403 of 458) were on polypharmacy, with 29% (118 of 403) using concomitant enzyme inducers. Only 38% (175 of 458) of the concentrations were therapeutic, with 53% (244 of 458) being subtherapeutic. Drug concentration and concentration-to-dose ratio were highly variable among individuals in all 6 ASMs. CONCLUSIONS.­: A simple and rapid LC-MS/MS method for TDM of 6 ASMs was developed and successfully applied to clinical practice. This large-scale TDM data could help establish an effective monitoring strategy for these drugs.

Identifying important factors for successful surgery in patients with lateral temporal lobe epilepsy.

OBJECTIVE: Lateral temporal lobe epilepsy (LTLE) has been diagnosed in only a small number of patients; therefore, its surgical outcome is not as well-known as that of mesial temporal lobe epilepsy. We aimed to evaluate the long-term (5 years) and short-term (2 years) surgical outcomes and identify possible prognostic factors in patients with LTLE. METHODS: This retrospective cohort study was conducted between January 1995 and December 2018 among patients who underwent resective surgery in a university-affiliated hospital. Patients were classified as LTLE if ictal onset zone was in lateral temporal area. Surgical outcomes were evaluated at 2 and 5 years. We subdivided based on outcomes and compared clinical and neuroimaging data including cortical thickness between two groups. RESULTS: Sixty-four patients were included in the study. The mean follow-up duration after the surgery was 8.4 years. Five years after surgery, 45 of the 63 (71.4%) patients achieved seizure freedom. Clinically and statistically significant prognostic factors for postsurgical outcomes were the duration of epilepsy before surgery and focal cortical dysplasia on postoperative histopathology at the 5-year follow-up. Optimal cut-off point for epilepsy duration was eight years after the seizure onset (odds ratio 4.375, p-value = 0.0214). Furthermore, we propose a model for predicting seizure outcomes 5 years after surgery using the receiver operating characteristic curve and nomogram (area under the curve = 0.733; 95% confidence interval, 0.588-0.879). Cortical thinning was observed in ipsilateral cingulate gyrus and contralateral parietal lobe in poor surgical group compared to good surgical group (p-value < 0.01, uncorrected). CONCLUSIONS: The identified predictors of unfavorable surgical outcomes may help in selecting optimal candidates and identifying the optimal timing for surgery among patients with LTLE. Additionally, cortical thinning was more extensive in the poor surgical group.

Surgical outcome and prognostic factors in epilepsy patients with MR-negative focal cortical dysplasia.

OBJECTIVE: Focal cortical dysplasia (FCD) represents a heterogeneous group of disorders of the cortical formation and is one of the most common causes of epilepsy. Magnetic resonance imaging (MRI) is the modality of choice for detecting structural lesions, and the surgical prognosis in patients with MR lesions is favorable. However, the surgical prognosis of patients with MR-negative FCD is unknown. We aimed to evaluate the long-term surgical outcomes and prognostic factors in MR-negative FCD patients through comprehensive presurgical data. METHODS: We retrospectively reviewed data from 719 drug-resistant epilepsy patients who underwent resective surgery and selected cases in which surgical specimens were pathologically confirmed as FCD Type I or II. If the epileptogenic focus and surgical specimens were obtained from brain areas with a normal MRI appearance, they were classified as MR-negative FCD. Surgical outcomes were evaluated at 2 and 5 years, and clinical, neurophysiological, and neuroimaging data of MR-negative FCD were compared to those of MR-positive FCD. RESULTS: Finally, 47 MR-negative and 34 MR-positive FCD patients were enrolled in the study. The seizure-free rate after surgery (Engel classification I) at postoperative 2 year was 59.5% and 64.7% in the MR-negative and positive FCD groups, respectively (p = 0.81). This rate decreased to 57.5% and 44.4% in the MR-negative and positive FCD groups (p = 0.43) at postoperative 5 years. MR-negative FCD showed a higher proportion of FCD type I (87.2% vs. 50.0%, p = 0.001) than MR-positive FCD. Unilobar cerebral perfusion distribution (odds ratio, OR 5.41) and concordance of interictal epileptiform discharges (OR 5.10) were significantly associated with good surgical outcomes in MR-negative FCD. CONCLUSION: In this study, MR-negative and positive FCD patients had a comparable surgical prognosis, suggesting that comprehensive presurgical evaluations, including multimodal neuroimaging studies, are crucial for obtaining excellent surgical outcomes even in epilepsy patients with MR-negative FCD.

Defining the optimal target for anterior thalamic deep brain stimulation in patients with drug-refractory epilepsy.

OBJECTIVE: The anterior thalamic nucleus (ATN) is a common target for deep brain stimulation (DBS) for the treatment of drug-refractory epilepsy. However, no atlas-based optimal DBS (active contacts) target within the ATN has been definitively identified. The object of this retrospective study was to analyze the relationship between the active contact location and seizure reduction to establish an atlas-based optimal target for ATN DBS. METHODS: From among 25 patients who had undergone ATN DBS surgery for drug-resistant epilepsy between 2016 and 2018, those who had follow-up evaluations for more than 1 year were eligible for study inclusion. After an initial stimulation period of 6 months, patients were classified as responsive (≥ 50% median decrease in seizure frequency) or nonresponsive (< 50% median decrease in seizure frequency) to treatment. Stimulation parameters and/or active contact positions were adjusted in nonresponsive patients, and their responsiveness was monitored for at least 1 year. Postoperative CT scans were coregistered nonlinearly with preoperative MR images to determine the center coordinate and atlas-based anatomical localizations of all active contacts in the Montreal Neurological Institute (MNI) 152 space. RESULTS: Nineteen patients with drug-resistant epilepsy were followed up for at least a year following bilateral DBS electrode implantation targeting the ATN. Active contacts located more adjacent to the center of gravity of the anterior half of the ATN volume, defined as the anterior center (AC), were associated with greater seizure reduction than those not in this location. Intriguingly, the initially nonresponsive patients could end up with much improved seizure reduction by adjusting the active contacts closer to the AC at the final postoperative follow-up. CONCLUSIONS: Patients with stimulation targeting the AC may have a favorable seizure reduction. Moreover, the authors were able to obtain additional good outcomes after electrode repositioning in the initially nonresponsive patients. Purposeful and strategic trajectory planning to target this optimal region may predict favorable outcomes of ATN DBS.

The Role of Anterior Thalamic Deep Brain Stimulation as an Alternative Therapy in Patients with Previously Failed Vagus Nerve Stimulation for Refractory Epilepsy.

Deep brain stimulation (DBS) has provided new treatment options for refractory epilepsy; however, treatment outcomes of DBS in refractory epilepsy patients previously treated with vagus nerve stimulation (VNS) have not been clarified. Herein, treatment outcomes of DBS of the anterior nucleus of the thalamus (ANT-DBS) in patients who had previously experienced VNS failure are reported. Seven patients who had previously experienced VNS failure underwent ANT-DBS device implantation. VNS was turned off before DBS device implantation. Monthly seizure counts starting from baseline to 12-18 months after DBS were analyzed. Five (71.3%) of the 7 patients experienced a >50% reduction of seizure counts after DBS; 1 responder reached a seizure-free status after DBS therapy. Of the 2 nonresponders, 1 subject showed improvement in seizure strength and duration, which lessened the impact of the seizures on the patient's quality of life. This is the first study in which favorable outcomes of ANT-DBS surgery were observed in individual patients with refractory epilepsy who had not responded to prior VNS. Further studies with a larger number of subjects and longer follow-up period are needed to confirm the feasibility of ANT-DBS in patients who have previously experienced VNS failure.

High Frequency Oscillations in Epilepsy: Detection Methods and Considerations in Clinical Application.

High frequency oscillations (HFOs) is a brain activity observed in electroencephalography (EEG) in frequency ranges between 80-500 Hz. HFOs can be classified into ripples (80-200 Hz) and fast ripples (200-500 Hz) by their distinctive characteristics. Recent studies reported that both ripples and fast fipples can be regarded as a new biomarker of epileptogenesis and ictogenesis. Previous studies verified that HFOs are clinically important both in patients with mesial temporal lobe epilepsy and neocortical epilepsy. Also, in epilepsy surgery, patients with higher resection ratio of brain regions with HFOs showed better outcome than a group with lower resection ratio. For clinical application of HFOs, it is important to delineate HFOs accurately and discriminate them from artifacts. There have been technical improvements in detecting HFOs by developing various detection algorithms. Still, there is a difficult issue on discriminating clinically important HFOs among detected HFOs, where both quantitative and subjective approaches are suggested. This paper is a review on published HFO studies focused on clinical findings and detection techniques of HFOs as well as tips for clinical applications.

Prognostic factors determining poor postsurgical outcomes of mesial temporal lobe epilepsy.

OBJECTIVES: To investigate the long-term postoperative outcomes and predictive factors associated with poor surgical outcomes in mesial temporal lobe epilepsy (MTLE). MATERIALS AND METHODS: We enrolled patients with MTLE who underwent resective surgery at single university-affiliated hospital. Surgical outcomes were determined using a modified Engel classification at the 2nd and 5th years after surgery and the last time of follow-up. RESULTS: The mean duration of follow-up after surgery was 7.6 ± 3.7 years (range, 5.0-21.0 years). 334 of 400 patients (83.5%) were seizure-free at the 5th postoperative year. Significant predictive factors of a poor outcome at the 5th year were a history of generalized tonic clonic (GTC) seizures (odds ratio, OR; 2.318), bi-temporal interictal epileptiform discharge (IED) (OR; 3.107), bilateral hippocampal sclerosis (HS) (OR; 5.471), unilateral HS and combined extra-hippocampal lesion (OR; 5.029), and bi-temporal hypometabolism (BTH) (OR; 4.438). Bi-temporal IED (hazard ratio, HR; 2.186), BTH (HR; 2.043), bilateral HS (HR; 2.541) and unilateral HS and combined extra-hippocampal lesion (HR; 2.75) were independently associated with seizure recurrence. We performed a subgroup analysis of 208 patients with unilateral HS, and their independent predictors of a poor outcome at the 5th year were BTH (OR; 5.838) and tailored hippocampal resection (OR; 11.053). CONCLUSION: This study demonstrates that 16.5% of MTLE patients had poor long-term outcomes after surgery. Bilateral involvement in electrophysiological and imaging studies predicts poor surgical outcomes in MTLE patients.

Thalamo-cortical network underlying deep brain stimulation of centromedian thalamic nuclei in intractable epilepsy: a multimodal imaging analysis.

OBJECTIVE: Deep brain stimulation (DBS) of the centromedian thalamic nucleus (CM) can be an alternative treatment option for intractable epilepsy patients. Since CM may be involved in widespread cortico-subcortical networks, identification of the cortical sub-networks specific to the target stimuli may provide further understanding on the underlying mechanisms of CM DBS. Several brain structures have distinguishing brain connections that may be related to the pivotal propagation and subsequent clinical effect of DBS. METHODS: To explore core structures and their connections relevant to CM DBS, we applied electroencephalogram (EEG) and diffusion tensor imaging (DTI) to 10 medically intractable patients - three generalized epilepsy (GE) and seven multifocal epilepsy (MFE) patients unsuitable for resective surgery. Spatiotemporal activation pattern was mapped from scalp EEG by delivering low-frequency stimuli (5 Hz). Structural connections between the CM and the cortical activation spots were assessed using DTI. RESULTS: We confirmed an average 72% seizure reduction after CM DBS and its clinical efficiency remained consistent during the observation period (mean 21 months). EEG data revealed sequential source propagation from the anterior cingulate, followed by the frontotemporal regions bilaterally. In addition, maximal activation was found in the left cingulate gyrus and the right medial frontal cortex during the right and left CM stimulation, respectively. From DTI data, we confirmed concrete structural connections between CM and those maximal activation spots identified from EEG data. CONCLUSION: These results suggest that the anterior cingulate can be a core cortical structure for the bilateral propagation of CM stimulation. Our DTI findings also indicate that the propagation of CM stimulation may rely upon integrity of structural connections between CM and these key cortical regions. Structures and their connections found in this study may be relevant in the interpretation of the clinical outcomes of CM DBS.

Lacosamide and Levetiracetam Have No Effect on Sharp-Wave Ripple Rate.

Pathological high-frequency oscillations are a novel marker used to improve the delineation of epileptogenic tissue and, hence, the outcome of epilepsy surgery. Their practical clinical utilization is curtailed by the inability to discriminate them from physiological oscillations due to frequency overlap. Although it is well documented that pathological HFOs are suppressed by antiepileptic drugs (AEDs), the effect of AEDs on normal HFOs is not well known. In this experimental study, we have explored whether physiological HFOs (sharp-wave ripples) of hippocampal origin respond to AED treatment. The results show that application of a single dose of levetiracetam or lacosamide does not reduce the rate of sharp-wave ripples. In addition, it seems that these new generation drugs do not negatively affect the cellular and network mechanisms involved in sharp-wave ripple generation, which may provide a plausible explanation for the absence of significant negative effects on cognitive functions of these drugs, particularly on memory.

Intractable Epilepsy with Solitary Cerebral Calcification.

Cerebral calcification is a common incidental finding upon brain imaging and its epileptogenicity is often underestimated. Here, we report a case of intractable epilepsy arising in conjunction with a solitary cerebral calcification. A 42-year-old male with intractable epilepsy was admitted to the epilepsy clinic for invasive epilepsy surgery. Brain magnetic resonance imaging revealed a slight high-intensity signal change in the right amygdala and a small, calcified lesion in the right lateral temporal region. The patient underwent invasive monitoring with subdural electrodes. He had five habitual seizures with automatisms and fast activity. These seizures initiated in the right lateral temporal area just above the solitary calcified lesion. Neuropathology of the calcified lesion showed no specific findings apart from a fibrocalcific nodule. Thus, although solitary cerebral calcifications may be an asymptomatic or coincidental finding in some patients, they may also have a highly epileptogenic focus.

Accuracy of MEG in localizing irritative zone and seizure onset zone: Quantitative comparison between MEG and intracranial EEG.

BACKGROUND: We conducted the study to examine accuracy of the magnetoencephalography (MEG) spike source localization in presurgical evaluation of patients with medically refractory focal epilepsy. METHODS: Ten consecutive patients with refractory focal epilepsy who were candidates for two-stage surgery with long-term intracranial electroencephalography (ICEEG) monitoring were enrolled. Interictal MEG recordings with simultaneous scalp EEG were obtained within 7days before the ICEEG electrode implantation. The location of each MEG spike source was quantitatively compared with ICEEG spike foci (focal area of interictal spikes) and ICEEG ictal foci (earliest cortical origin of seizures). Gyral-width concordance and sublobar concordance were also determined for all MEG spike sources. Gyral-width concordance was defined by distance of 15mm or less between MEG spike sources and ICEEG spike foci or ICEEG ictal foci. RESULTS: Visual analyses of the MEG traces of all 10 patients revealed 292 spikes (29.2±24.0 per patient). Spike yield of the MEG was similar to the simultaneously recorded scalp EEG. MEG spike sources were closely located with ICEEG spike foci (distance: 9.3±10.8mm). Clustered MEG spike sources were even closer to ICEEG spike foci (distance: 7.3±6.4mm). MEG spike sources, even clustered ones, were less concordant with ICEEG ictal foci and had significant longer distance from ICEEG ictal foci (distance: 21.5±15.6mm for all sources, 19.7±13.7mm for clustered sources). Gyral-width concordance rate and sublobar concordance rate were also higher with ICEEG interictal spike foci than with ICEEG ictal foci. On the other hand, 53.4% of interictal spike foci from ICEEG were not detected by interictal MEG recordings. CONCLUSIONS: MEG spike sources, especially clustered ones, from interictal recording could localize the irritative zone of ICEEG with a high accuracy. However, MEG spike sources have relatively poor correlation with seizure onset zone and lower sensitivity in identifying all irritative zones of ICEEG. This limitation should be considered in the interpretation of MEG results.

Prognostic Role of Functional Neuroimaging after Multilobar Resection in Patients with Localization-Related Epilepsy.

To investigate the usage of functional neuroimaging as a prognostic tool for seizure recurrence and long-term outcomes in patients with multilobar resection, we recruited 90 patients who received multilobar resections between 1995 and 2013 with at least 1-year follow-up (mean 8.0 years). All patients were monitored using intracranial electroencephalography (EEG) after pre-surgical evaluation. Clinical data (demographics, electrophysiology, and neuroimaging) were reviewed retrospectively. Surgical outcomes were evaluated at 1, 2, 5 years after surgery, and at the end of the study. After 1 year, 56 patients (62.2%) became Engel class I and at the last follow-up, 47 patients (52.2%) remained seizure-free. Furthermore, non-localized 18F-fluorodeoxyglucose positron emission tomography (PET), identifying hypometabolic areas not concordant with ictal onset zones, significantly correlated with seizure recurrence after 1 year. Non-lesional magnetic resonance imaging (MRI) and left-sided resection correlated with poor outcomes. In the last follow-up, non-localized PET and left-sided resection significantly correlated with seizure recurrence. Both localized PET and ictal-interictal SPECT subtraction co-registered to MR (SISCOM) predicted good surgical outcomes in the last follow-up (69.2%, Engel I). This study suggests that PET and SISCOM may predict postoperative outcomes for patients after multilobar epilepsy and shows comparable long-term surgical outcomes after multilobar resection.

EEG Source Imaging in Partial Epilepsy in Comparison with Presurgical Evaluation and Magnetoencephalography.

BACKGROUND AND PURPOSE: The aim of this study was to determine the usefulness of three-dimensional (3D) scalp EEG source imaging (ESI) in partial epilepsy in comparison with the results of presurgical evaluation, magnetoencephalography (MEG), and electrocorticography (ECoG). METHODS: The epilepsy syndrome of 27 partial epilepsy patients was determined by presurgical evaluations. EEG recordings were made using 70 scalp electrodes, and the 3D coordinates of the electrodes were digitized. ESI images of individual and averaged spikes were analyzed by Curry software with a boundary element method. MEG and ECoG were performed in 23 and 9 patients, respectively. RESULTS: ESI and MEG source imaging (MSI) results were well concordant with the results of presurgical evaluations (in 96.3% and 100% cases for ESI and MSI, respectively) at the lobar level. However, there were no spikes in the MEG recordings of three patients. The ESI results were well concordant with MSI results in 90.0% of cases. Compared to ECoG, the ESI results tended to be localized deeper than the cortex, whereas the MSI results were generally localized on the cortical surface. ESI was well concordant with ECoG in 8 of 9 (88.9%) cases, and MSI was also well concordant with ECoG in 4 of 5 (80.0%) cases. The EEG single dipoles in one patient with mesial temporal lobe epilepsy were tightly clustered with the averaged dipole when a 3 Hz high-pass filter was used. CONCLUSIONS: The ESI results were well concordant with the results of the presurgical evaluation, MSI, and ECoG. The ESI analysis was found to be useful for localizing the seizure focus and is recommended for the presurgical evaluation of intractable epilepsy patients.

Resection of individually identified high-rate high-frequency oscillations region is associated with favorable outcome in neocortical epilepsy.

OBJECTIVES: High-frequency oscillations (HFOs) represent a novel electrophysiologic marker of endogenous epileptogenicity. Clinically, this propensity can be utilized to more accurately delineate the resection margin before epilepsy surgery. Currently, prospective application of HFOs is limited because of a lack of an exact quantitative measure to reliably identify HFO-generating areas necessary to include in the resection. Here, we evaluated the potential of a patient-individualized approach of identifying high-rate HFO regions to plan the neocortical resection. METHODS: Fifteen patients with neocortical seizure-onset zones (SOZs) underwent intracranial electroencephalographic monitoring. To identify interictal HFOs, we applied an automated, hypersensitive HFO-detection algorithm followed by post hoc processing steps to reject false detections. The spatial relationship between HFO distribution and the SOZ was evaluated. To address high interpatient variability in HFO properties, we evaluated the high-rate HFO region, an unbiased statistical parameter, in each patient. The relationship between resection of the high-rate HFO region and postoperative outcome was examined. RESULTS: Grouped data demonstrated that the rate of ripple (60-200 Hz) and fast ripple (200-500 Hz) was increased in the SOZ (both p < 0.01). Intrapatient analysis of the HFO distribution localized the SOZ in 11 patients. High-rate HFO regions were determined in all patients by an individually adjusted threshold. Resection of high-rate HFO regions was significantly associated with a seizure-free outcome (p < 0.01). The extent/ratio of SOZ or spiking region resection did not differ between seizure-free and seizure-persistent groups. SIGNIFICANCE: Intrapatient analysis of high-rate HFOs provides more detailed description of HFO-generating areas and can mark the areas of clinically significant epileptogenicity--a crucial component of the neocortical epileptic network that should be removed to achieve a good outcome. Validating and adopting an unbiased quantitative HFO parameter has the potential to propel wider and prospective utilization of HFOs in the surgical treatment of neocortical epilepsy and to improve its outcome.

Mirror focus in a patient with intractable occipital lobe epilepsy.

Mirror focus is one of the evidence of progression in epilepsy, and also has practical points for curative resective epilepsy surgery. The mirror foci are related to the kindling phenomena that occur through interhemispheric callosal or commissural connections. A mirror focus means the secondary epileptogenic foci develop in the contralateral hemispheric homotopic area. Thus mirror foci are mostly reported in patients with temporal or frontal lobe epilepsy, but not in occipital lobe epilepsy. We have observed occipital lobe epilepsy with mirror focus. Before epilepsy surgery, the subject's seizure onset zone was observed in the left occipital area by ictal studies. Her seizures abated for 10 months after the resection of left occipital epileptogenic focus, but recurred then. The recurred seizures were originated from the right occipital area which was in the homotopic contralateral area. This case can be an evidence that occipital lobe epilepsy may have mirror foci, even though each occipital lobe has any direct interhemispheric callosal connections between them.

Is an epilepsy presurgical evaluation necessary for mid-grade and high-grade brain tumors presenting with seizures?

Patients with epilepsy caused by mid-grade and high-grade tumors do not usually undergo formal presurgical epilepsy evaluations before tumor resection. However, a minority of these patients may benefit significantly from just such a structured presurgical evaluation especially when seizure freedom or seizure reduction is a surgical aim in addition to total tumor resection. Typical cases comprise patients with multifocal tumors, tumors with bilateral extension, tumors over eloquent cortex, and the need for differentiation of spells of an uncertain nature, for example, epileptic versus psychogenic nonepileptic seizures. If they are epileptic, the definition of the epileptic lesion versus the epileptogenic zone and eloquent cortex can be another reason for monitoring. In addition to noninvasive recordings, invasive studies that use subdural or depths electrodes can be of special importance in these patients, leading to an exact delineation of the epileptogenic zone, usually extending beyond the epileptic lesion, and allow safe differentiation of epileptic from eloquent cortex.

Long-Term Outcome of Vagus Nerve Stimulation for Refractory Epilepsy: A Longitudinal 4 year Follow-up Study in Korea.

BACKGROUND AND PURPOSE: We evaluated the long-term outcome of patients with refractory epilepsy who were treated with vagus nerve stimulation (VNS). METHODS: This investigation is designed as an uncontrolled, open-label, retrospective and long-term study. From June 1999 to October 2009, 20 patients were suitable for inclusion criteria: 4-year follow-up and documented seizure frequency before and after implantation. Seizure frequency was collected by clinical recording and interview. Primary outcome measures were the reduction in mean seizure frequency and responder rate (seizure frequency reduction of >50%). RESULTS: In 20 patients (M:F=16:4), mean age at the time of implantation was 22.3 years (range 8-44) and mean disease duration was 13.9 years (range 1-37). Mean maximum stimulation output current was 1.90 mA (range 0.25-3.5). Overall mean seizure frequency reduction rate was 61.8% at 4 year follow-up comparison with baseline (p<0.001). Proposition of responder (> 50% seizure frequency reduction) of yearly follow-up were 40 % at 1 yr, 50% at 2 yrs, 45% at 3 yrs, and 60% at 4 yrs. There was no difference of stimulation parameter between the responders and non-responders. CONCLUSIONS: Long-term outcome of VNS suggests that VNS is an effective treatment option that can be alternative to surgery in patients with refractory epilepsy.

Identification of TSC1 and TSC2 mutations in Korean patients with tuberous sclerosis complex.

Tuberous sclerosis complex is a genetic disorder caused by mutations in the genes TSC1 or TSC2. Studies of these mutations are very rare in Korean populations. A previous study identified mutations in only 30% of patients by denaturing high performance liquid chromatography with sequencing. Here, we sought to determine the mutational frequency in Koreans. Eleven patients who fulfilled the diagnostic criteria for tuberous sclerosis complex were included. All patients underwent sequencing of both TSC genes, and if no mutations were evident, multiplex ligation-dependent probe amplification was performed. Mutations were detected by sequencing in 82% (9/11) of patients: 36.4% (4/11) in TSC1 and 45.5% (5/11) in TSC2. Two patients with no mutations carried large deletions that included exon 1 of TSC1 in one patient and exons 1-15 of TSC2 in the other patient. Mutations were completely identified in the present study. Therefore, mutation rates in Korean patients may not be lower than those in other ethnic groups. Direct sequencing followed by multiplex ligation-dependent probe amplification analysis may constitute a rational approach to identify disease-causing mutations in Korean patients.

Seizure localization in patients with multiple tubers: presurgical evaluation in tuberous sclerosis.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder. Epileptic seizure is the most common neurological symptom. Medically intractable epilepsy in these patients is candidates of epilepsy surgery. We report two cases of TSC with ictal electroencephalography (EEG) arising from right temporal lobe who underwent video-EEG monitoring. Two of these patients were first diagnosed with TSC at age 30 and 23 years old, partly because of their mild accompanying symptoms other than epileptic seizures. Case 1 had a long history of epilepsy since three years old. Although she had multiple cortical tubers on her magnetic resonance imaging (MRI) scan, all the recorded ictal and interictal EEG indicated epileptic focus on right temporal region, suggesting that cortical tuber located at the anterior temporal region as epileptogenic tuber. Case 2 also had long history of epilepsy since three years old. His brain MRI revealed numerous tubers in his brain including one at the right hippocampus. His ictal EEG originated from right temporal area, suggesting hippocampus as epileptic focus. Epileptic focus in TSC are commonly localized to one of the multiple cortical tubers, which is epileptogenic. The localization of epileptogenic zone can be aided with interictal and ictal EEG, brain MRI, subtracted ictal-interictal SPECT co-registered with MRI (SISOM) and positron emission tomography (PET).

Evaluation of algorithms for intracranial EEG (iEEG) source imaging of extended sources: feasibility of using iEEG source imaging for localizing epileptogenic zones in secondary generalized epilepsy.

Precise identification of epileptogenic zones in patients with intractable drug-resistant epilepsy is critical for successful epilepsy surgery. Numerous source-imaging algorithms for localizing epileptogenic zones based on scalp electroencephalography (EEG) and magnetoencephalography (MEG) have been developed and validated in simulation and experimental studies. Recently, intracranial EEG (iEEG)-based imaging of epileptogenic sources has attracted interest as a promising tool for presurgical evaluation of epilepsy; however, most iEEG studies have focused on localization of epileptogenic zones in focal epilepsy. In the present study, we investigated whether iEEG source imaging is a useful supplementary tool for identifying extended epileptogenic sources in secondary generalized epilepsy such as Lennox-Gastaut syndrome (LGS). To this end, we applied four different cortical source imaging algorithms, namely minimum norm estimation (MNE), low-resolution electromagnetic tomography (LORETA), standardized LORETA (sLORETA), and L(p)-norm estimation (p = 1.5, referred to as Lp1.5), to artificial iEEG datasets generated assuming various source sizes and locations. We also applied these four algorithms to clinical ictal iEEG recordings acquired from a pediatric patient with LGS. Interestingly, the traditional MNE algorithm outperformed the other imaging algorithms in most of our experiments, particularly in cases when larger-sized sources were activated. Although sLORETA outperformed both LORETA and Lp1.5, its performance was not as good as that of MNE. Compared to the other algorithms, the performance of Lp1.5 decayed most rapidly as the source size increased. Our findings suggest that iEEG source imaging using MNE is a promising auxiliary tool for the identification of epileptogenic zones in secondary generalized epilepsy. We anticipate that our results will provide useful guidelines for selection of an appropriate imaging algorithm for iEEG source imaging studies.