Investigating the effect of hippocampal sclerosis on parietal memory network.

OBJECTIVE: We aimed to investigate differences in episodic memory networks between patients with temporal lobe epilepsy (TLE) due to hippocampal sclerosis and healthy controls, especially with regards to the parietal memory network (PMN), as well as their relation to neuropsychological memory performance after mesial temporal resection. METHODS: 28 healthy subjects as well as 21 patients with TLE (12 left, 9 right) were investigated using a spatial memory fMRI paradigm, which has been shown to activate the PMN. Regions of interest (ROI) were defined based on the results of the second-level analyses and activations within the predefined ROIs were compared across groups and correlated with postoperative verbal and nonverbal memory scores. RESULTS: Healthy subjects showed activations within regions belonging to the dorsal visual stream and the PMN as well as the bilateral parahippocampal place area, the bilateral frontal eye field, and the bilateral middle frontal gyrus. Comparison between groups revealed that TLE patients activated significantly less in the left middle occipital gyrus and the right precuneus. The activation pattern in left TLE patients showed further reductions, mainly in areas belonging to the dorsal visual stream and the PMN within the left hemisphere. Activations within the left superior parietal lobulus, bilateral inferior parietal lobulus, bilateral middle temporal gyrus, left precuneus, left frontal eye field, and left middle frontal gyrus correlated significantly with postoperative verbal memory scores, and activations within the left superior parietal lobulus, left inferior parietal lobulus, left middle temporal gyrus, and left precuneus correlated significantly with higher performance in postoperative nonverbal memory scores. SIGNIFICANCE: The PMN is involved in episodic memory encoding. Higher activations in areas belonging to the PMN and the dorsal visual stream, especially within the left hemisphere, before amygdalohippocampectomy may result in higher postoperative memory scores. PLAIN LANGUAGE SUMMARY: This study aims to investigate the effects of epilepsy due to hippocampal sclerosis, i.e. scarring in the temporal lobe, on memory networks in the brain. We discovered that especially patients with left-sided hippocampal sclerosis show reduced brain activations in visual areas and memory networks within the left hemisphere of the brain during orientation in space. Importantly, higher activations within these areas may result in better memory after epilepsy surgery.

Robot-assisted stereoencephalography vs subdural electrodes in the evaluation of temporal lobe epilepsy.

OBJECTIVE: Invasive video-electroencephalography (iVEEG) is the gold standard for evaluation of refractory temporal lobe epilepsy before second stage resective surgery (SSRS). Traditionally, the presumed seizure onset zone (SOZ) has been covered with subdural electrodes (SDE), a very invasive procedure prone to complications. Temporal stereoelectroencephalography (SEEG) with conventional frame-based stereotaxy is time-consuming and impeded by the geometry of the frame. The introduction of robotic assistance promised a simplification of temporal SEEG implantation. However, the efficacy of temporal SEEG in iVEEG remains unclear. The aim of this study was therefore to describe the efficiency and efficacy of SEEG in iVEEG of temporal lobe epilepsy. METHODS: This retrospective study enrolled 60 consecutive patients with medically intractable epilepsy who underwent iVEEG of a potential temporal SOZ by SDE (n = 40) or SEEG (n = 20). Surgical time efficiency was analyzed by the skin-to-skin time (STS) and the total procedure time (TPT) and compared between groups (SDE vs SEEG). Surgical risk was depicted by the 90-day complication rate. Temporal SOZ were treated by SSRS. Favorable outcome (Engel°1) was assessed after 1 year of follow-up. RESULTS: Robot-assisted SEEG significantly reduced the duration of surgery (STS and TPT) compared to SDE implantations. There was no significant difference in complication rates. Notably, all surgical revisions in this study were attributed to SDE. Unilateral temporal SOZ was detected in 34/60 cases. Of the 34 patients, 30 underwent second stage SSRS. Both SDE and SEEG had a good predictive value for the outcome of temporal SSRS with no significant group difference. SIGNIFICANCE: Robot-assisted SEEG improves the accessibility of the temporal lobe for iVEEG by increasing surgical time efficiency and by simplifying trajectory selection without losing its predictive value for SSRS.

Deep Brain Stimulation of the Anterior Nucleus of the Thalamus in Drug-Resistant Epilepsy in the MORE Multicenter Patient Registry.

BACKGROUND AND OBJECTIVES: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice. METHODS: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes. RESULTS: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years (p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years (p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported. DISCUSSION: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy. TRIAL REGISTRATION INFORMATION: MORE ClinicalTrials.gov Identifier: NCT01521754, first posted on January 31, 2012.

Frame-based and robot-assisted insular stereo-electroencephalography via an anterior or posterior oblique approach.

OBJECTIVE: There is an increasing interest in stereo-electroencephalography (SEEG) for invasive evaluation of insular epilepsy. The implantation of insular SEEG electrodes, however, is still challenging due to the anatomical location and complex functional segmentation in both an anteroposterior and ventrodorsal (i.e., superoinferior) direction. While the orthogonal approach (OA) is the shortest trajectory to the insula, it might insufficiently cover these networks. In contrast, the anterior approach (AOA) or posterior oblique approach (POA) has the potential for full insular coverage, with fewer electrodes bearing a risk of being more inaccurate due to the longer trajectory. Here, the authors evaluated the implantation accuracy and the detection of epilepsy-related SEEG activity with AOA and POA insular trajectories. METHODS: This retrospective study evaluated the accuracy of 220 SEEG electrodes in 27 patients. Twelve patients underwent a stereotactic frame-based procedure (frame group), and 15 patients underwent a frameless robot-assisted surgery (robot group). In total, 55 insular electrodes were implanted using the AOA or POA considering the insular anteroposterior and ventrodorsal functional organization. The entry point error (EPE) and target point error (TPE) were related to the implantation technique (frame vs robot), the length of the trajectory, and the location of the target (insular vs noninsular). Finally, the spatial distribution of epilepsy-related SEEG activity within the insula is described. RESULTS: There were no significant differences in EPE (mean 0.9 ± 0.6 for the nonsinsular electrodes and 1.1 ± 0.7 mm for the insular electrodes) and TPE (1.5 ± 0.8 and 1.6 ± 0.9 mm, respectively), although the length of trajectories differed significantly (34.1 ± 10.9 and 70.1 ± 9.0 mm, repsectively). There was a significantly larger EPE in the frame group than in the robot group (1.5 ± 0.6 vs 0.7 ± 0.5 mm). However, there was no group difference in the TPE (1.5 ± 0.8 vs 1.6 ± 0.8 mm). Epilepsy-related SEEG activity was detected in 42% (23/55) of the insular electrodes. Spatial distribution of this activity showed a clustering in both anteroposterior and ventrodorsal directions. In purely insular onset cases, subsequent insular lesionectomy resulted in a good seizure outcome. CONCLUSIONS: The implantation of insular electrodes via the AOA or POA is safe and efficient for SEEG implantation covering both anteroposterior and ventrodorsal functional organization with few electrodes. In this series, there was no decrease in accuracy due to the longer trajectory of insular SEEG electrodes in comparison with noninsular SEEG electrodes. The results of frame-based and robot-assisted implantations were comparable.

Desynchronization of temporal lobe theta-band activity during effective anterior thalamus deep brain stimulation in epilepsy.

BACKGROUND: Bilateral cyclic high frequency deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) reduces the seizure count in a subset of patients with epilepsy. Detecting stimulation-induced alterations of pathological brain networks may help to unravel the underlying physiological mechanisms related to effective stimulation delivery and optimize target engagement. METHODS: We acquired 64-channel electroencephalography during ten ANT-DBS cycles (145 â€‹Hz, 90 â€‹µs, 3-5 â€‹V) of 1-min ON followed by 5-min OFF stimulation to detect changes in cortical activity related to seizure reduction. The study included 14 subjects (three responders, four non-responders, and seven healthy controls). Mixed-model ANOVA tests were used to compare differences in cortical activity between subgroups both ON and OFF stimulation, while investigating frequency-specific effects for the seizure onset zones. RESULTS: ANT-DBS had a widespread desynchronization effect on cortical theta and alpha band activity in responders, but not in non-responders. Time domain analysis showed that the stimulation induced reduction in theta-band activity was temporally linked to the stimulation period. Moreover, stimulation induced theta-band desynchronization in the temporal lobe channels correlated significantly with the therapeutic response. Responders to ANT-DBS and healthy-controls had an overall lower level of theta-band activity compared to non-responders. CONCLUSION: This study demonstrated that temporal lobe channel theta-band desynchronization may be a predictive physiological hallmark of therapeutic response to ANT-DBS and may be used to improve the functional precision of this intervention by verifying implantation sites, calibrating stimulation contacts, and possibly identifying treatment responders prior to implantation.

Clinical application of advanced MR methods in children: points to consider.

The application of both functional MRI and diffusion MR tractography prior to a neurosurgical operation is well established in adults, but less so in children, for several reasons. For this review, we have identified several aspects (task design, subject preparation, actual scanning session, data processing, interpretation of results, and decision-making) where pediatric peculiarities should be taken into account. Further, we not only systematically identify common issues, but also provide solutions, based on our experience as well as a review of the pertinent literature. The aim is to provide the clinician as well as the imaging scientist with information that helps to plan, conduct, and interpret such a clinically-indicated exam in a way that maximizes benefit for, and minimizes the burden on the individual child.

Face-name association task reveals memory networks in patients with left and right hippocampal sclerosis.

We aimed to identify reorganization processes of episodic memory networks in patients with left and right temporal lobe epilepsy (TLE) due to hippocampal sclerosis as well as their relations to neuropsychological memory performance. We investigated 28 healthy subjects, 12 patients with left TLE (LTLE) and 9 patients with right TLE (RTLE) with hippocampal sclerosis by means of functional magnetic resonance imaging (fMRI) using a face-name association task, which combines verbal and non-verbal memory functions. Regions-of-interest (ROIs) were defined based on the group results of the healthy subjects. In each ROI, fMRI activations were compared across groups and correlated with verbal and non-verbal memory scores. The face-name association task yielded activations in bilateral hippocampus (HC), left inferior frontal gyrus (IFG), left superior frontal gyrus (SFG), left superior temporal gyrus, bilateral angular gyrus (AG), bilateral medial prefrontal cortex and right anterior temporal lobe (ATL). LTLE patients demonstrated significantly less activation in the left HC and left SFG, whereas RTLE patients showed significantly less activation in the HC bilaterally, the left SFG and right AG. Verbal memory scores correlated with activations in the left and right HC, left SFG and right ATL and non-verbal memory scores with fMRI activations in the left and right HC and left SFG. The face-name association task can be employed to examine functional alterations of hippocampal activation during encoding of both verbal and non-verbal material in one fMRI paradigm. Further, the left SFG seems to be a convergence region for encoding of verbal and non-verbal material.

Risk Factors of Preoperative and Early Postoperative Seizures in Patients with Meningioma: A Retrospective Single-Center Cohort Study.

OBJECTIVE: Well-defined risk factors for the identification of patients with meningioma who might benefit from preoperative or early postoperative seizure prophylaxis are unknown. We investigated and quantified risk factors to determine individual risks of seizure occurrence in patients with meningioma. METHODS: A total of 634 adult patients with meningioma were included in this retrospective cohort study. Patient gender and age, tumor location, grade and volume, usage of antiepileptic drugs (AEDs) and extent of resection were determined. RESULTS: Preoperative and early postoperative seizures occurred in 15% (n = 97) and 5% (n = 21) of the patients, respectively. Overall, 502 and 418 patients were eligible for multivariate logistic regression analyses of preoperative and early postoperative seizures, respectively. Male gender (odds ratio [OR], 2.06; P = 0.009), a non-skull base location (OR, 4.43; P < 0.001), and a tumor volume of >8 cm3 (OR, 3.05; P = 0.002) were associated with a higher risk of preoperative seizures and were used to stratify the patients into 3 prognostic groups. The high-risk subgroup of patients with meningioma showed a seizure rate of >40% (OR, 9.8; P < 0.001). Only a non-skull base tumor location (OR, 2.61; P = 0.046) was identified as a significant risk factor for early postoperative seizures. AEDs did not reduce early postoperative seizure occurrence. CONCLUSIONS: Seizure prophylaxis might be considered for patients at high risk of developing seizures who are for other reasons being considered for watchful waiting instead of resection. In contrast, our data do not provide any evidence of the efficacy of perioperative AEDs in patients with meningioma.

Multimodal Assessment Reveals Late-Onset Hemispheric Shift of Language in a Child with Meningocerebral Dysplasia.

We report on a girl with progressive left frontal tissue destruction starting at the age of almost 8 years. She manifested acutely with epileptic seizures accompanied by Broca aphasia as well as transient right hemiparesis. Due to refractory epilepsy developing over the next years, which originated from the left frontal lobe, the decision was made to proceed to epilepsy surgery. By then, her language functions had recovered despite progressive left frontal tissue-destruction, raising the possibility of a hemispheric shift of language. Clinical functional magnetic resonance imaging (fMRI) was conducted to localize brain regions involved in language production. A complex pattern of clear right-hemispheric dominance, but with some left-sided contribution was found. However, a Wada test suggested the left hemisphere to be critical, seemingly contradicting fMRI. Invasive electroencephalogram recordings could reconcile these results by identifying the fMRI-detected, residual left-sided activation as being relevant for speech production. Only by combining the localizing information from fMRI with the information obtained by two invasive procedures could the unusual pattern of late-onset language reorganization be uncovered. This allowed for extensive left frontal resection, with histology confirming meningocerebral angiodysplasia. Postoperatively, language functions were preserved and seizure outcome was excellent. The implications of our findings for presurgical assessments in children are discussed.

Predictors of preoperative and early postoperative seizures in patients with intra-axial primary and metastatic brain tumors: A retrospective observational single center study.

OBJECTIVE: Antiepileptic treatment of brain tumor patients mainly depends on the individual physician's choice rather than on well-defined predictive factors. We investigated the predictive value of defined clinical parameters to formulate a model of risk estimations for subpopulations of brain tumor patients. METHODS: We enclosed 650 patients > 18 years of age who underwent brain tumor surgery and included a number of clinical data. Logistic regressions were performed to determine the effect sizes of seizure-related risk factors and to develop prognostic scores for the occurrence of preoperative and early postoperative seizures. RESULTS: A total of 492 patients (334 gliomas) were eligible for logistic regression for preoperative seizures, and 338 patients for early postoperative seizures. Age ≤ 60 years (odds ratio [OR] = 1.66, p = 0.020), grades I and II glioma (OR = 4.00, p = 0.0002), total tumor/edema volume ≤ 64cm(3) (OR = 2.18, p = 0.0003), and frontal location (OR = 2.28, p = 0.034) demonstrated an increased risk for preoperative seizures. Isocitrate-dehydrogenase mutations (OR = 2.52, p = 0.026) were an independent risk factor in the glioma subgroup. Age ≥ 60 years (OR = 3.32, p = 0.041), total tumor/edema volume ≤ 64cm(3) (OR = 3.17, p = 0.034), complete resection (OR = 15.50, p = 0.0009), diencephalic location (OR = 12.2, p = 0.013), and high-grade tumors (OR = 5.67, p = 0.013) were significant risk factors for surgery-related seizures. Antiepileptics (OR = 1.20, p = 0.60) did not affect seizure occurrence. For seizure occurrence, patients could be stratified into 3 prognostic preoperative and into 2 prognostic early postoperative groups. INTERPRETATION: Based on the developed prognostic scores, seizure prophylaxis should be considered in high-risk patients and patient stratification for prospective studies may be feasible in the future.

Multimodal effective connectivity analysis reveals seizure focus and propagation in musicogenic epilepsy.

Dynamic causal modeling (DCM) is a method to non-invasively assess effective connectivity between brain regions. 'Musicogenic epilepsy' is a rare reflex epilepsy syndrome in which seizures can be elicited by musical stimuli and thus represents a unique possibility to investigate complex human brain networks and test connectivity analysis tools. We investigated effective connectivity in a case of musicogenic epilepsy using DCM for fMRI, high-density (hd-) EEG and MEG and validated results with intracranial EEG recordings. A patient with musicogenic seizures was examined using hd-EEG/fMRI and simultaneous '256-channel hd-EEG'/'whole head MEG' to characterize the epileptogenic focus and propagation effects using source analysis techniques and DCM. Results were validated with invasive EEG recordings. We recorded one seizure with hd-EEG/fMRI and four auras with hd-EEG/MEG. During the seizures, increases of activity could be observed in the right mesial temporal region as well as bilateral mesial frontal regions. Effective connectivity analysis of fMRI and hd-EEG/MEG indicated that right mesial temporal neuronal activity drives changes in the frontal areas consistently in all three modalities, which was confirmed by the results of invasive EEG recordings. Seizures thus seem to originate in the right mesial temporal lobe and propagate to mesial frontal regions. Using DCM for fMRI, hd-EEG and MEG we were able to correctly localize focus and propagation of epileptic activity and thereby characterize the underlying epileptic network in a patient with musicogenic epilepsy. The concordance between all three functional modalities validated by invasive monitoring is noteworthy, both for epileptic activity spread as well as for effective connectivity analysis in general.

Incipient preoperative reorganization processes of verbal memory functions in patients with left temporal lobe epilepsy.

We previously reported nonlinear correlations between verbal episodic memory performance and BOLD signal in memory fMRI in healthy subjects. The purpose of the present study was to examine this observation in patients with left mesial temporal lobe epilepsy (mTLE) who often experience memory decline and need reliable prediction tools before epilepsy surgery with hippocampectomy. Fifteen patients with left mTLE (18-57years, nine females) underwent a verbal memory fMRI paradigm. Correlations between BOLD activity and neuropsychological data were calculated for the i) hippocampus (HC) as well as ii) extrahippocampal mTL structures. Memory performance was systematically associated with activations within the right HC as well as with activations within the left extrahippocampal mTL regions (amygdala and parahippocampal gyrus). As hypothesized, the analyses revealed cubic relationships, with one peak in patients with marginal memory performance and another peak in patients with very good performance. The nonlinear correlations between memory performance and activations might reflect the compensatory recruitment of neural resources to maintain memory performance in patients with ongoing memory deterioration. The present data suggest an already incipient preoperative reorganization process of verbal memory in non-amnesic patients with left mTLE by simultaneously tapping the resources of the right HC and left extrahippocampal mTL regions. Thus, in the preoperative assessment, both neuropsychological performance and memory fMRI should be considered together.

Proposal: different types of alteration and loss of consciousness in epilepsy.

There are at least five types of alterations of consciousness that occur during epileptic seizures: auras with illusions or hallucinations, dyscognitive seizures, epileptic delirium, dialeptic seizures, and epileptic coma. Each of these types of alterations of consciousness has a specific semiology and a distinct pathophysiologic mechanism. In this proposal we emphasize the need to clearly define each of these alterations/loss of consciousness and to apply this terminology in semiologic descriptions and classifications of epileptic seizures. The proposal is a consensus opinion of experienced epileptologists, and it is hoped that it will lead to systematic studies that will allow a scientific characterization of the different types of alterations/loss of consciousness described in this article.

Nonlinear correlations impair quantification of episodic memory by mesial temporal BOLD activity.

OBJECTIVE: Episodic memory processes can be investigated using different functional MRI (fMRI) paradigms. The purpose of the present study was to examine correlations between neuropsychological memory test scores and BOLD signal changes during fMRI scanning using three different memory tasks. METHOD: Twenty-eight right-handed healthy subjects underwent three paradigms, (a) a word pair, (b) a space-labyrinth, and (c) a face-name association paradigm. These paradigms were compared for their value in memory quantification and lateralization by calculating correlations between the BOLD signals in the mesial temporal lobe and behavioral data derived from a neuropsychological test battery. RESULTS: As expected, group analysis showed left-sided activation for the verbal, a tendency to right-sided activation for the spatial, and bilateral activation for the face-name paradigm. No linear correlations were observed between neuropsychological data and activation in the temporo-mesial region. However, we found significant u-shaped correlations between behavioral memory performance and activation in both the verbal and the face-name paradigms, that is, BOLD signal changes were greater not only among participants who performed best on the neuropsychological tests, but also among the poorest performers. The figural learning task did not correlate with the activations in the space-labyrinth paradigm at all. CONCLUSIONS: We interpreted the u-shaped correlations to be due to compensatory hippocampal activations associated with low performance when people try unsuccessfully to remember presented items. Because activation levels did not linearly increase with memory performance, the latter cannot be quantified by fMRI alone, but only be used in conjunction with neuropsychological testing.

BOLD signal in memory paradigms in hippocampal region depends on echo time.

PURPOSE: To evaluate the hypothesis that the entire hippocampus might be affected by susceptibility artifacts. Previous studies described susceptibility artifacts in the amygdala and the anterior hippocampus. MATERIALS AND METHODS: We investigated 20 subjects with a verbal memory paradigm aiming at testing two different TEs (45 vs. 64 msec) at 1.5 T for hippocampal blood oxygenation level-dependent (BOLD) activity. T2* maps were calculated from the normalized mean echo-planar imaging (EPI) of the two echo times (TEs). RESULTS: Within the hippocampal region of interest (ROI), the amount of suprathreshold voxels was significantly higher at TE = 64 msec compared to TE = 45 msec. When corrected for multiple comparisons (family-wise error [FWE] in a small volume of interest, P < 0.05) we no longer found significant activations at TE = 45 msec, while a significant number of voxels remained after the small volume correction (P < 0.05, FWE) within the ROI at TE = 64 msec. CONCLUSION: Although a shorter TE demonstrates advantages, a TE of 45 msec leads to a significant loss of BOLD signal detection in memory functional magnetic resonance imaging (fMRI) studies when compared to 64 msec. We assume that the hippocampal region, even the anterior part, is not strongly affected by susceptibility gradients.

Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins.

PURPOSE: Rasmussen encephalitis (RE) leads to progressive tissue and function loss of one brain hemisphere and often intractable epilepsy. This is the first randomized prospective treatment trial in RE. METHODS: Germany-wide, patients with suspected recent-onset RE were recruited and if eligible randomized to tacrolimus or intravenous immunoglobulins (IVIGs). A loss of motor function or hemispheric volume by ≥ 15% (in patients >12 years at disease onset: ≥ 8%) led to study exit. Untreated patients served as a historical control group. KEY FINDINGS: Over 6.3 years, 21 patients with recent-onset RE were identified. Sixteen were randomized to tacrolimus (n = 9) or IVIG (n = 7). Immunotreated patients had a longer "survival" than the historical controls. Neither treatment was more efficacious than the other. Two tacrolimus patients experienced serious adverse events. No immunotreated but several untreated patients developed intractable epilepsy. No patient with refractory epilepsy became treatment-responsive under immunotherapy. SIGNIFICANCE: The countrywide incidence rate of diagnosed RE is estimated as 2.4 cases/107 people ≤ age 18/year. Treatment with tacrolimus or IVIG may slow down tissue and function loss and prevent development of intractable epilepsy. However, immunotherapy may "arrest" patients in a dilemma state of pharmacoresistant epilepsy but too good function to be offered functional hemispherectomy. These compounds may therefore contribute to the therapeutic armamentarium for RE patients without difficult-to-treat epilepsies.

Targeted next generation sequencing as a diagnostic tool in epileptic disorders.

PURPOSE: Epilepsies have a highly heterogeneous background with a strong genetic contribution. The variety of unspecific and overlapping syndromic and nonsyndromic phenotypes often hampers a clear clinical diagnosis and prevents straightforward genetic testing. Knowing the genetic basis of a patient's epilepsy can be valuable not only for diagnosis but also for guiding treatment and estimating recurrence risks. METHODS: To overcome these diagnostic restrictions, we composed a panel of genes for Next Generation Sequencing containing the most relevant epilepsy genes and covering the most relevant epilepsy phenotypes known so far. With this method, 265 genes were analyzed per patient in a single step. We evaluated this panel on a pilot cohort of 33 index patients with concise epilepsy phenotypes or with a severe but unspecific seizure disorder covering both sporadic and familial cases. KEY FINDINGS: We identified presumed disease-causing mutations in 16 of 33 patients comprising sequence alterations in frequently as well as in less commonly affected genes. The detected aberrations encompassed known and unknown point mutations (SCN1A p.R222X, p. E289V, p.379R, p.R393H; SCN2A p.V208E; STXBP1 p.R122X; KCNJ10 p.L68P, p.I129V; KCTD7 p.L108M; KCNQ3 p.P574S; ARHGEF9 p.R290H; SMS p.F58L; TPP1 p.Q278R, p.Q422H; MFSD8 p.T294K), a putative splice site mutation (SCN1A c.693A> p.T/P231P) and small deletions (SCN1A p.F1330Lfs3X [1 bp]; MFSD8 p.A138Dfs10X [7 bp]). All mutations have been confirmed by conventional Sanger sequencing and, where possible, validated by parental testing and segregation analysis. In three patients with either Dravet syndrome or myoclonic epilepsy, we detected SCN1A mutations (p.R222X, p.P231P, p.R393H), even though other laboratories had previously excluded aberrations of this gene by Sanger sequencing or high-resolution melting analysis. SIGNIFICANCE: We have developed a fast and cost-efficient diagnostic screening method to analyze the genetic basis of epilepsies. We were able to detect mutations in patients with clear and with unspecific epilepsy phenotypes, to uncover the genetic basis of many so far unresolved cases with epilepsy including mutation detection in cases in which previous conventional methods yielded falsely negative results. Our approach thus proved to be a powerful diagnostic tool that may contribute to collecting information on both common and unknown epileptic disorders and in delineating associated phenotypes of less frequently mutated genes.

Intravenous and oral levetiracetam in patients with a suspected primary brain tumor and symptomatic seizures undergoing neurosurgery: the HELLO trial.

BACKGROUND: Levetiracetam (LEV) is a newer anticonvulsant with a favorable safety profile. There seem to be no relevant drug interactions, and an intravenous formulation is available. Therefore, LEV might be a suitable drug for the perioperative anticonvulsive therapy of patients with suspected brain tumors undergoing neurosurgery. METHODS: In this prospective study (NCT00571155) patients with suspected primary brain tumors and tumor-related seizures were perioperatively treated with oral and intravenous LEV up to 4 weeks before and until 4 weeks after a planned neurosurgical procedure. FINDINGS: Thirty patients with brain tumor-related seizures and intended neurosurgery were included. Three patients did not undergo the scheduled surgery after enrollment, and two patients were lost to follow-up. Therefore, 25 patients were fully evaluable. After initiation of therapy with LEV, 100% of the patients were seizure-free in the pre-surgery phase (3 days up to 4 weeks before surgery), 88% in the 48 h post-surgery phase and 84% in the early follow-up phase (48 h to 4 weeks post surgery). Treatment failure even after dose escalation to 3,000 mg/day occurred in three patients. No serious adverse events related to the treatment with LEV occurred. CONCLUSION: Our data show the feasibility and safety of oral and intravenous LEV in the perioperative treatment of tumor-related seizures. Although this was a single arm study, the efficacy of LEV appears promising. Considering the side effects and interactions of other anticonvulsants, LEV seems to be a favorable option in the perioperative treatment of brain tumor-related seizures.

Chronic high-frequency deep brain stimulation of the STN/SNr for progressive myoclonic epilepsy.

Chronic high-frequency deep brain stimulation (DBS) may also be effective in patients with refractory epilepsy. A possible benefit has been postulated because of the connections that exist between the subthalamic nucleus (STN) and the superior colliculus. Individual case reports and pilot studies of successful DBS in different types of epilepsy have already been presented. Here, the case of a 39-year-old male with progressive myoclonic epilepsy is reported who remained severely impaired despite VNS and combined antiepileptic drug therapy. Bilateral DBS electrodes were implanted into the STN, followed by implantation of a neurostimulation system under general anesthesia. Adjustment and testing of the remaining contacts was done over several months postoperatively. Bilateral monopolar DBS reduced the intensity and frequency of seizures by 50%. The patient has so far been followed for 12 months. This is the first report of positive effects of DBS in progressive myoclonic epilepsy in an adult patient. A subsequent prospective study will have to investigate whether the STN or other target nuclei are most suitable for DBS in these types of epilepsy and which long-term results can be obtained.

Clinical characteristics in focal cortical dysplasia: a retrospective evaluation in a series of 120 patients.

Focal cortical dysplasias (FCDs) are increasingly diagnosed as a cause of symptomatic focal epilepsy in paediatric and adult patients. However, little is known about the clinical characteristics of epilepsy in these patients. In order to elucidate the clinical characteristics of their epilepsy, 120 pharmacoresistant patients including children and adults with histologically proven FCD were studied retrospectively. Age at seizure onset was analysed in the total group and compared between subgroups with different localization and different histological subtypes of FCD. The role of febrile seizures with respect to dual pathology was investigated. Seizure semiology was analysed focusing on initial seizure type and change of seizure semiology during the course of disease. Finally, transient responsiveness to antiepileptic drug therapy was studied. In the majority of patients, epilepsy began in the first 5 years of life. However, onset of epilepsy could also occur in the second or third decade until the age of 60. Age at epilepsy onset was not significantly different between temporal, extratemporal and multilobar localization of FCD. Patients without cytoarchitectural abnormalities (mild malformations of cortical development, FCD 1a according to Palmini) had significantly later epilepsy onset (P= 0.001) compared with patients with cytoarchitectural abnormalities (FCD 1b, 2a and 2b according to Palmini). In patients with additional hippocampal sclerosis (dual pathology) febrile seizures were significantly more frequently reported (P = 0.02) than in patients without dual pathology. Moreover, patients with dual pathology and febrile seizures significantly more frequently presented with severe hippocampal sclerosis (Wyler Grade 3-4) as compared with patients with dual pathology in the absence of febrile seizures (P = 0.03). First observed seizures were mainly tonic or generalized tonic-clonic. A change of seizure semiology seemed to be age-dependent and occurred between the age of >1 and 14 years. About 15.8% of the patients presented with status epilepticus during the course of disease. About 17% of the patients showed transient responsiveness (> or =1 year seizure freedom) to antiepileptic drug therapy either after initial therapy (50%) or later in the course of epilepsy (50%). Patients with FCD represent a heterogeneous group. Different age at epilepsy onset and transient responsiveness to antiepileptic drugs in approximately 17% of patients may reflect different dynamics in epileptogenicity of the underlying FCD. Dual pathology may be associated with different pathomechanisms in patients with and without febrile seizures.