MP2RAGE vs. MPRAGE surface-based morphometry in focal epilepsy.

In drug-resistant focal epilepsy, detecting epileptogenic lesions using MRI poses a critical diagnostic challenge. Here, we assessed the utility of MP2RAGE-a T1-weighted sequence with self-bias correcting properties commonly utilized in ultra-high field MRI-for the detection of epileptogenic lesions using a surface-based morphometry pipeline based on FreeSurfer, and compared it to the common approach using T1w MPRAGE, both at 3T. We included data from 32 patients with focal epilepsy (5 MRI-positive, 27 MRI-negative with lobar seizure onset hypotheses) and 94 healthy controls from two epilepsy centres. Surface-based morphological measures and intensities were extracted and evaluated in univariate GLM analyses as well as multivariate unsupervised 'novelty detection' machine learning procedures. The resulting prediction maps were analyzed over a range of possible thresholds using alternative free-response receiver operating characteristic (AFROC) methodology with respect to the concordance with predefined lesion labels or hypotheses on epileptogenic zone location. We found that MP2RAGE performs at least comparable to MPRAGE and that especially analysis of MP2RAGE image intensities may provide additional diagnostic information. Secondly, we demonstrate that unsupervised novelty-detection machine learning approaches may be useful for the detection of epileptogenic lesions (maximum AFROC AUC 0.58) when there is only a limited lesional training set available. Third, we propose a statistical method of assessing lesion localization performance in MRI-negative patients with lobar hypotheses of the epileptogenic zone based on simulation of a random guessing process as null hypothesis. Based on our findings, it appears worthwhile to study similar surface-based morphometry approaches in ultra-high field MRI (≥ 7 T).

Effects of inverse methods and spike phases on interictal high-density EEG source reconstruction.

OBJECTIVE: To determine the effect of inverse methods and timepoints of interictal epileptic discharges (IEDs) used for high-density electric source imaging (hd-ESI) in pharmacoresistant focal epilepsies. METHODS: We retrospectively evaluated the hd-ESI and [18F]fluorodeoxyglucose positron emission tomography (18FDG-PET) of 21 operated patients with pharmacoresistant focal epilepsy (Engel I). Volumetric hd-ESI was performed with three different inverse methods such as the inverse solution linearly constrained minimum variance (LCMV, a beamformer method), standardized low resolution electromagnetic tomography (sLORETA) and weighted minimum-norm estimation (wMNE) and at different IED phases. Hd-ESI accuracy was determined by volumetric overlap and distance between hd-ESI source maximum, as well as 18FDG-PET hypometabolic region relative to the resection zone (RZ). RESULTS: In our cohort, the shortest distances and greatest volumetric overlaps to the RZ were found in the half-rise and peak-phase for all inverse methods. The distance to the RZ was not different between the centroid of the clinical hypothesis-based cluster and the source maximum in peak-phase. However, the distance of the hypothesis-based cluster was significantly shorter compared to the cluster selected by the smallest p-value. CONCLUSIONS: Hd-ESI provides the greatest accuracy in determining the RZ at the IED half-rise and peak-phase for all applied inverse methods, whereby sLORETA and LCMV were equally accurate. SIGNIFICANCE: Our results offer guidance in selecting inverse methods and IED phases for hd-ESI, compare the performance of hd-ESI and 18FDG-PET and encourage future studies in investigating the relationship between interictal ESI and 18FDG-PET hypometabolism.

Comparison of Resting-State EEG Network Analyses With and Without Parallel MRI in Genetic Generalized Epilepsy.

Genetic generalized epilepsy (GGE) is conceptualized as a brain disorder involving distributed bilateral networks. To study these networks, simultaneous EEG-fMRI measurements can be used. However, inside-MRI EEG suffers from strong MR-related artifacts; it is not established whether EEG-based metrics in EEG-fMRI resting-state measurements are suitable for the analysis of group differences at source-level. We evaluated the impact of the inside-MR measurement condition on statistical group comparisons of EEG on source-level power and functional connectivity in patients with GGE versus healthy controls. We studied the cross-modal spatial relation of statistical group differences in seed-based FC derived from EEG and parallel fMRI. We found a significant increase in power and a frequency-specific change in functional connectivity for the inside MR-scanner compared to the outside MR-scanner condition. For power, we found reduced group difference between GGE and controls both in terms of statistical significance as well as effect size. Group differences for ImCoh remained similar both in terms of statistical significance as well as effect size. We found increased seed-based FC for GGE patients from the thalamus to the precuneus cortex region in fMRI, and in the theta band of simultaneous EEG. Our findings suggest that the analysis of EEG functional connectivity based on ImCoh is suitable for MR-EEG, and that relative group difference in a comparison of patients with GGE against controls are preserved. Spatial correspondence of seed-based FC group differences between the two modalities was found for the thalamus.

Feasibility of high-density electric source imaging in the presurgical workflow: Effect of number of spikes and automated spike detection.

OBJECTIVE: Presurgical high-density electric source imaging (hdESI) of interictal epileptic discharges (IEDs) is only used by few epilepsy centers. One obstacle is the time-consuming workflow both for recording as well as for visual review. Therefore, we analyzed the effect of (a) an automated IED detection and (b) the number of IEDs on the accuracy of hdESI and time-effectiveness. METHODS: In 22 patients with pharmacoresistant focal epilepsy receiving epilepsy surgery (Engel 1) we retrospectively detected IEDs both visually and semi-automatically using the EEG analysis software Persyst in 256-channel EEGs. The amount of IEDs, the Euclidean distance between hdESI maximum and resection zone, and the operator time were compared. Additionally, we evaluated the intra-individual effect of IED quantity on the distance between hdESI maximum of all IEDs and hdESI maximum when only a reduced amount of IEDs were included. RESULTS: There was no significant difference in the number of IEDs between visually versus semi-automatically marked IEDs (74 ± 56 IEDs/patient vs 116 ± 115 IEDs/patient). The detection method of the IEDs had no significant effect on the mean distances between resection zone and hdESI maximum (visual: 26.07 ± 31.12 mm vs semi-automated: 33.6 ± 34.75 mm). However, the mean time needed to review the full datasets semi-automatically was shorter by 275 ± 46 min (305 ± 72 min vs 30 ± 26 min, P < 0.001). The distance between hdESI of the full versus reduced amount of IEDs of the same patient was smaller than 1 cm when at least a mean of 33 IEDs were analyzed. There was a significantly shorter intraindividual distance between resection zone and hdESI maximum when 30 IEDs were analyzed as compared to the analysis of only 10 IEDs (P < 0.001). SIGNIFICANCE: Semi-automatized processing and limiting the amount of IEDs analyzed (~30-40 IEDs per cluster) appear to be time-saving clinical tools to increase the practicability of hdESI in the presurgical work-up.

A novel likely pathogenic heterozygous HECW2 missense variant in a family with variable expressivity of neurodevelopmental delay, hypotonia, and epileptiform EEG patterns.

Pathogenic variants in HECW2 are extremely rare. So far, only 19 cases have been reported. They were associated with epilepsy, intellectual disability, absent language, hypotonia, and autism. As these cases were all de novo mutations, mostly presenting without identical variants, variable expressivity has never been investigated. Here, we describe the first family with the same novel variant in HECW2. A 19-year old female patient presented with bursts of generalized spike-wave discharges and intellectual disability. We performed next-generation-sequencing, to detect the genetic cause. Next-generation-sequencing revealed a novel likely pathogenic variant in HECW2 (c.3571C>T; p.Arg1191Trp) in the index patient, her mother and brother. They showed some similar phenotypic patterns with intellectual disability, hypotonia and generalized epileptiform patterns. However, the mother was less severely affected and epileptiform patterns were less frequent. The brother presented with additional autistic features. In contrast to previous cases, the speech of all individuals was only mildly impaired. This is the first case report of a family with the same novel likely pathogenic variant in HECW2 and as such provides insight into the phenotypic variability of this mutation. The expressivity of symptoms may be so mild that genetic and EEG analysis are needed to disclose the correct diagnosis.

Prophylactic Palmitoylethanolamide Prolongs Survival and Decreases Detrimental Inflammation in Aged Mice With Bacterial Meningitis.

Easy-to-achieve interventions to promote healthy longevity are desired to diminish the incidence and severity of infections, as well as associated disability upon recovery. The dietary supplement palmitoylethanolamide (PEA) exerts anti-inflammatory and neuroprotective properties. Here, we investigated the effect of prophylactic PEA on the early immune response, clinical course, and survival of old mice after intracerebral E. coli K1 infection. Nineteen-month-old wild type mice were treated intraperitoneally with two doses of either 0.1 mg PEA/kg in 250 µl vehicle solution (n = 19) or with 250 µl vehicle solution only as controls (n = 19), 12 h and 30 min prior to intracerebral E. coli K1 infection. The intraperitoneal route was chosen to reduce distress in mice and to ensure exact dosing. Survival time, bacterial loads in cerebellum, blood, spleen, liver, and microglia counts and activation scores in the brain were evaluated. We measured the levels of IL-1ß, IL-6, MIP-1α, and CXCL1 in cerebellum and spleen, as well as of bioactive lipids in serum in PEA- and vehicle-treated animals 24 h after infection. In the absence of antibiotic therapy, the median survival time of PEA-pre-treated infected mice was prolonged by 18 h compared to mice of the vehicle-pre-treated infected group (P = 0.031). PEA prophylaxis delayed the onset of clinical symptoms (P = 0.037). This protective effect was associated with lower bacterial loads in the spleen, liver, and blood compared to those of vehicle-injected animals (P ≤ 0.037). PEA-pre-treated animals showed diminished levels of pro-inflammatory cytokines and chemokines in spleen 24 h after infection, as well as reduced serum concentrations of arachidonic acid and of one of its metabolites, 20-hydroxyeicosatetraenoic acid. In the brain, prophylactic PEA tended to reduce bacterial titers and attenuated microglial activation in aged infected animals (P = 0.042). Our findings suggest that prophylactic PEA can counteract infection associated detrimental responses in old animals. Accordingly, PEA treatment slowed the onset of infection symptoms and prolonged the survival of old infected mice. In a clinical setting, prophylactic administration of PEA might extend the potential therapeutic window where antibiotic therapy can be initiated to rescue elderly patients.

The Early Adaptive Immune Response in the Pathophysiological Process of Pneumococcal Meningitis.

BACKGROUND: The adaptive immune system has been considered to play a minimal role in the early host response during bacterial meningitis. METHODS: We investigated the progression and outcome of pneumococcal meningitis in Rag1-/- mice lacking functional B and T cells by assessing overall and symptom-free survival, bacteriological and histological studies, as well as flow cytometry and measurements of proinflammatory mediators. RESULTS: The intracerebral injection of S. pneumoniae D39 induced the recruitment of B and T cells (CD4+, γδ and natural killer) into the brain of wild-type mice. Mice with no functional B and T cells developed clinical symptoms and succumbed to the infection earlier than the wild-type group. In the CNS, Rag1-/- mice showed lower levels of interleukin 1ß, reduced microglial proliferation, and impaired granulocyte recruitment with an earlier spread of pneumococci into the bloodstream, compared with wild-type mice. Lack of B and T cells resulted in a severe impairment of bacterial clearance in blood, spleen, and liver and an exaggerated systemic inflammatory response. CONCLUSIONS: B and T cells are important effector cells delaying the spread of pneumococci from the brain to the systemic circulation and shaping the immune response, thereby prolonging the survival of the host in the absence of antibiotic treatment.