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Background Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) can serve as a valuable tool in optimising and individualising epilepsy treatment, especially in vulnerable groups such as pregnant women, the elderly and children. Unfortunately, TDM is often performed suboptimally due to limitations in blood collection. Therefore, we investigated volumetric absorptive micro sampling (VAMS) – a new home-sampling technique. We aimed to evaluate VAMS to determine and quantify the different AEDs and concentrations of 16 different AEDs in whole blood collected by VAMS. Methods Patient blood samples (n = 138) were collected via venepunctures at the Academic Centre for Epileptology Kempenhaeghe. AED concentrations were determined, and these concentrations were used to compare the VAMS method (whole blood) with the conventional method (serum). In addition, the recovery was examined as well as the impact of haematocrit. Finally, AED-spiked blood was used to test the stability of the AEDs inside the micro-sampler devices over a period of time and whether temperature had an effect on the stability. Results VAMS allows for an accurate detection of 16 different AEDs within 2 days after sampling. Deviation in recovery was less than 10% and high correlations were found between VAMS and conventional sampling. Moreover, haematocrit does not have an effect with values between 0.3 and 0.5 (L/L). Finally, although storage temperature of VAMS does affect some AEDs, most are unaffected. Conclusions VAMS enables an accurate detection of a wide variety of AEDs within 2 days after sampling.

Diagnostic Exome Sequencing in 100 Consecutive Patients With Both Epilepsy and Intellectual Disability Snoeijen-Schouwenaars FM, van Ool JS, Verhoeven JS, et al. Epilepsia. 2019;60(1):155-164. doi:10.1111/epi.14618. Epub December 7, 2018. PMID: 30525188.Objective:Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole-exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy.Methods:One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. Whole-exome sequencing analysis was performed in 2 steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. Results: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 (40%) of 25 patients with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future.Significance:This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield. Diagnostic Yield of Genetic Tests in Epilepsy: A Meta-Analysis and Cost-Effectiveness Study Sánchez Fernández I, Loddenkemper T, Gaínza-Lein M, Sheidley BR, Poduri A. Neurology. 2019. Epub ahead of print. pii: 10.1212/WNL.0000000000006850. doi:10.1212/WNL.0000000000006850. PMID: 30610098 Objective:To compare the cost-effectiveness of genetic testing strategies in patients with epilepsy of unknown etiology.Methods:This meta-analysis and cost-effectiveness study compared strategies involving 3 genetic tests: chromosomal microarray (CMA), epilepsy panel (EP) with deletion/duplication testing, and whole-exome sequencing (WES) in a cost-effectiveness model, using “no genetic testing”“ as a point of comparison.Results:Twenty studies provided information on the diagnostic yield of CMA (8 studies), EP (9 studies), and WES (6 studies). The diagnostic yield was highest for WES: 0.45 (95% confidence interval [CI]: 0.33-0.57; 0.32 [95% CI: 0.22-0.44] adjusting for potential publication bias), followed by EP: 0.23 (95% CI: 0.18-0.29) and CMA: 0.08 (95% CI: 0.06-0.12). The most cost-effective test was WES with an incremental cost-effectiveness ratio (ICER) of US$15 000/diagnosis. However, after adjusting for potential publication bias, the most cost-effective test was EP (ICER: US$15 848/diagnosis) followed by WES (ICER: US$34 500/diagnosis). Among combination strategies, the most cost-effective strategy was WES, then if nondiagnostic, EP, then if nondiagnostic, CMA (ICER: US$15 336/diagnosis); although adjusting for potential publication bias, the most cost-effective strategy was EP ± CMA ± WES (ICER: US$18 385/diagnosis). Although the cost-effectiveness of individual tests and testing strategies overlapped, CMA was consistently less cost-effective than WES and EP.Conclusion:Whole-exome sequencing and EP are the most cost-effective genetic tests for epilepsy. Our analyses support for a broad population of patients with unexplained epilepsy, starting with these tests. Although less expensive, CMA has lower yield, and its use as the first-tier test is thus not supported from a cost-effectiveness perspective.

ObjectiveThis nationwide cohort study evaluates seizure responses to immunotherapy and antiepileptic drugs (AEDs) in patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), and anti-gamma-aminobutyric-acid B receptor (GABABR) encephalitis.MethodsAnti-LGI1, anti-NMDAR, and anti-GABABR encephalitis patients with new-onset seizures were included. Medical information about disease course, AEDs and immunotherapies used, effects, and side effects were collected. Outcome measures were (1) seizure freedom while using AEDs or immunotherapy, (2) days to seizure freedom from start of AEDs or immunotherapy, and (3) side effects.ResultsOf 153 patients with autoimmune encephalitis (AIE) (53 LGI1, 75 NMDAR, 25 GABABR), 72% (n = 110) had epileptic seizures, and 89% reached seizure freedom. At least 53% achieved seizure freedom shortly after immunotherapy, and 14% achieved seizure freedom while using only AEDs (p < 0.0001). This effect was similar in all types (p = 0.0001; p = 0.0005; p = 0.013, respectively). Median time to seizure freedom from AEDs start was 59 days (interquartile range [IQR] 27–160), and 28 days from start of immunotherapy (IQR 9–71, p < 0.0001). Side effects were psychotic behavior and suicidal thoughts by the use of levetiracetam, and rash by the use of carbamazepine. Carbamazepine was more effective than levetiracetam in reducing seizures in anti-LGI1 encephalitis (p = 0.031). Only 1 patient, of 86 surviving patients, developed epilepsy after resolved encephalitis.ConclusionEpilepsy after resolved encephalitis was rare in our cohort of patients with AIE treated with immunotherapy. In addition, seizure freedom is achieved faster and more frequently after immunotherapy. Therefore, AEDs should be considered as add-on treatment, and similar to treatment of other encephalitis symptoms, immunotherapy is crucial.

It is often difficult to predict seizure recurrence in subjects who have suffered a first-ever epileptic seizure. In this study, the predictive value of physiological signals measured using Electroencephalography (EEG) and functional MRI (fMRI) is assessed. In particular those patients developing epilepsy (i.e. a second unprovoked seizure) that were initially evaluated as having a low risk of seizure recurrence are of interest.In total, 26 epilepsy patients, of which 8 were initially evaluated as having a low risk of seizure recurrence (i.e. converters), and 17 subjects with only a single seizure were included. All subjects underwent routine EEG as well as fMRI measurements. For diagnostic classification, features related to the temporal dynamics were determined for both the processed EEG and fMRI data. Subsequently, a logistic regression classifier was trained on epilepsy and first-seizure subjects. The trained model was tested using the clinically relevant converters group.The sensitivity, specificity, and AUC (mean +/- SD) of the regression model including metrics from both modalities were 74 +/- 19%, 82 +/- 18%, and 0.75 +/- 0.12, respectively. Positive and negative predictive values (mean SD) of the regression model with both EEG and fMRI features are 84 +/- 14% and 78 +/- 12%. Moreover, this EEG/fMRI model showed significant improvements compared to the clinical diagnosis, whereas the models using metrics from either EEG or fMRI do not reach significance (p > 0.05).Temporal metrics computationally derived from EEG and fMRI time signals may clinically aid and synergistically improve the predictive value in a first-seizure sample. (C) 2020 The Author(s). Published by Elsevier Inc.

Highlights • This review discusses 16 studies using 7T MRI to evaluate patients with chronic focal epilepsy. • UHF MRI increases the sensitivity to detect an epileptogenic lesion. • Diagnostic gain of 7T over conventional MRI was between 8 and 67%, pooled gain was 31% • FCD, gliosis and HS were the most frequently diagnosed histopathological lesions. • No conclusion can be drawn whether 7T improves surgical treatment and seizure outcome., Rationale Resective epilepsy surgery is an evidence-based curative treatment option for patients with drug-resistant focal epilepsy. The major preoperative predictor of a good surgical outcome is detection of an epileptogenic lesion by magnetic resonance imaging (MRI). Application of ultra-high field (UHF) MRI, i.e. field strengths ≥ 7 Tesla (T), may increase the sensitivity to detect such a lesion. Methods A keyword search strategy was submitted to Pubmed, EMBASE, Cochrane Database and clinicaltrials.gov to select studies on UHF MRI in patients with epilepsy. Follow-up study selection and data extraction were performed following PRISMA guidelines. We focused on I) diagnostic gain of UHF- over conventional MRI, II) concordance of MRI-detected lesion, seizure onset zone and surgical decision-making, and III) postoperative histopathological diagnosis and seizure outcome. Results Sixteen observational cohort studies, all using 7T MRI were included. Diagnostic gain of 7T over conventional MRI ranged from 8% to 67%, with a pooled gain of 31%. Novel techniques to visualize pathological processes in epilepsy and lesion detection are discussed. Seizure freedom was achieved in 73% of operated patients; no seizure outcome comparison was made between 7T MRI positive, 7T negative and 3T positive patients. 7T could influence surgical decision-making, with high concordance of lesion and seizure onset zone. Focal cortical dysplasia (54%), hippocampal sclerosis (12%) and gliosis (8.1%) were the most frequently diagnosed histopathological entities. Significance UHF MRI increases, yet variably, the sensitivity to detect an epileptogenic lesion, showing potential for use in clinical practice. It remains to be established whether this results in improved seizure outcome after surgical treatment. Prospective studies with larger cohorts of epilepsy patients, uniform scan and sequence protocols, and innovative post-processing technology are equally important as further increasing field strengths. Besides technical ameliorations, improved correlation of imaging features with clinical semiology, histopathology and clinical outcome has to be established.

Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Objective: Currently, as evidence-based guidelines are lacking, in patients with poststroke epilepsy (PSE), the choice of the first antiepileptic drug (AED) is left over to shared decision by the treating physician and patient. Although, it is not uncommon that patients with PSE subsequently switch their first prescribed AED to another AED, reasons for those switches are not reported yet. In the present study, we therefore assessed the reasons for switching the first prescribed AED in patients with PSE.Method: We gathered a hospital-based case series of 53 adult patients with poststroke epilepsy and assessed the use of AEDs, comedication, and the reasons for switches between AEDs during treatment. We also determined the daily drug dose (DDD) at the switching moment.Results: During a median follow-up of 62 months (Interquartile range [IQR] 69 months), 21 patients (40%) switched their first prescribed AED. Seven patients switched AED at least once because of ineffectivity only or a combination of ineffectivity and side effects, whereas 14 patients switched AED at least once because of side effects only. The DDD was significantly (p Conclusion: In our case series, up to 40% of patients with epilepsy after stroke needed to switch their first prescribed AED, mostly because of side effects in lower dosage ranges. (C) 2019 The Authors. Published by Elsevier Inc.

Neuronal surface autoantibodies (NSAbs) against various antigens cause autoimmune encephalitis. Some of these antigens are also involved in the pathology of depression and anxiety. To study whether NSAbs are more common in plasma of individuals with depression and anxiety than in controls, and to investigate if NSAbs correlate with disease status, plasma samples of 819 individuals with a current diagnosis of depression and/or anxiety, 920 in remission and 492 individuals without these disorders were included in this study. Samples were tested by a combination of immunohistochemistry (IHC), staining on live rat hippocampus neurons and cell-based assay (CBA). By IHC, 50 (2.2%) samples showed immunoreactivity to rat brain tissue, with no significant differences between the aforementioned groups (22/819 vs 18/920 vs 11/492, P > 0.99). In addition, eight IHC positive samples were positive for NSAbs on live neurons (7/819 vs 0/920 vs 1/492, P = 0.006). The IHC-staining patterns of these eight samples were atypical for autoimmune encephalitis and accordingly, they tested negative for known NSAbs by CBA. No obvious difference in the clinical characteristics between individuals with or without NSAbs was observed. In conclusion, novel NSAbs were rare but predominately found in patients with current anxiety or depression indicating they might affect mental health in a small group of patients.

BackgroundDe novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia.ObjectivesTo delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations.MethodsDiagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes.ResultsWe report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes.ConclusionWe delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

Purpose The brains of patients with epilepsy may exhibit various morphological abnormalities, which are often not directly visible on structural MR images, as they may be focally subtle or related to a more large-scale inconspicuous disorganization of brain structures. To explore the relation between structural brain organization and epilepsy characteristics, including severity and cognitive co-morbidity, we determined structural covariance networks (SCNs). SCNs represent interregional correlations of morphologic measures, for instance in terms of cortical thickness, between various large-scale distributed brain regions. Methods Thirty-eight patients with focal seizures of all subtypes and 21 healthy controls underwent structural MRI, neurological, and IQ assessment. Cortical thickness was derived from the structural MRIs using FreeSurfer. Subsequently, SCNs were constructed on a group-level based on correlations of the cortical thicknesses between various brain regions. Individual SCNs for the epilepsy patients were extracted by adding the respective patient to the control group prior to the SCN construction (i.e. add-one-patient approach). Calculated network measures, i.e. path length, clustering coefficient and betweenness centrality were correlated with characteristics related to the severity of epilepsy, including seizure history and age at onset of epilepsy, and cognitive performance. Results Stronger clustering in the individual SCN was associated with a higher number of focal to bilateral tonic-clonic seizures during life time, a younger age at onset, and lower cognitive performance. The path length of the individual SCN was not related to the severity of epilepsy or cognitive performance. Higher betweenness centrality of the left cuneus and lower betweenness centrality of the right rostral middle frontal gyrus were associated with increased drug load and younger age at onset, respectively. Conclusions These results indicate that the correlations between interregional variations of cortical thickness reflect disease characteristics or responses to the disease and deficits in patients with epilepsy with focal seizures., Highlights • Interregional cortical thicknesses relations reflect the severity of epilepsy • Stronger clustering is associated with more seizures in patients with epilepsy • Stronger clustering is associated with younger onset age in patients with epilepsy • Stronger clustering is associated with lower IQ in patients with epilepsy • Betweenness centrality is associated with drug load and age at onset

Contains fulltext : 182353.pdf (Publisher’s version ) (Open Access) Seizures after intracerebral hemorrhage are repeatedly seen. Whether the development of seizures after intracerebral hemorrhage affects survival in the long term is unknown. This study aims to determine the relation between seizures (i.e., with and without anti-epileptic therapy) and long-term mortality risk in a large patient population with intracerebral hemorrhage. We retrospectively included patients with a non-traumatic ICH in all three hospitals in the South Limburg region in the Netherlands between January 1st 2004 and December 31st 2009, and we assessed all-cause mortality until March 14th 2016. Patient who did not survive the first seven days after intracerebral hemorrhage were excluded from analyses. We used Cox multivariate analyses to determine independent predictors of mortality. Of 1214 patients, 783 hemorrhagic stroke patients fulfilled the inclusion criteria, amongst whom 37 (4.7%) patients developed early seizures (within 7 days after hemorrhage) and 77 (9.8%) developed late seizures (more than 7 days after hemorrhage). Seizure development was not significantly related to mortality risk after correction for conventional vascular risk factors and hemorrhage severity. However, we found a small but independent relation between the use of anti-epileptic drugs and a lower long-term mortality (HR = 0.32, 95% CI 0.11-0.91). In our large population, seizures and epilepsy did not relate independently to an increased mortality risk after hemorrhage.

Objective: The diagnosis of epilepsy cannot be reliably made prior to a patient's second seizure in most cases. Therefore, adequate diagnostic tools are needed to differentiate subjects with a first seizure from those with a seizure preceding the onset of epilepsy. The objective was to explore spontaneous blood oxygen level-dependent (BOLD) fluctuations in subjects with a first-ever seizure and patients with new-onset epilepsy (NOE), and to find characteristic biomarkers for seizure recurrence after the first seizure.Methods: We examined 17 first-seizure subjects, 19 patients with new-onset epilepsy (NOE), and 18 healthy controls. All subjects underwent clinical investigation and received electroencephalography and resting-state functional magnetic resonance imaging (MRI). The BOLD time series were analyzed in terms of regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFFs).Results: We found significantly stronger amplitudes (higher fALFFs) in patients with NOE relative to first-seizure subjects and healthy controls. The frequency range of 73-198 mHz (slow-3 subband) appeared most useful for discriminating patients with NOE from first-seizure subjects. The ReHo measure did not show any significant differences.Significance: The fALFF appears to be a noninvasive measure that characterizes spontaneous BOLD fluctuations and shows stronger amplitudes in the slow-3 subband of patients with NOE relative first-seizure subjects and healthy controls. A larger study population with follow-up is required to determine whether fALFF holds promise as a potential biomarker for identifying subjects at increased risk to develop epilepsy.

Electrical stimulation mapping (ESM) is the gold standard for identification of “eloquent” areas prior to resection of epileptogenic tissue, however, it is time consuming and may cause side effects, especially stimulation-induced seizures and after-discharges. Broadband gamma activity (55 – 200 Hz) recorded with subdural electrocorticography (ECoG) during cognitive tasks has been proposed as an attractive tool for mapping cortical areas with specific function but until now has not proven definitive clinical value. Fewer studies have addressed whether the alpha (8 – 12 Hz) and beta (15 – 25 Hz) band activity could also be used to improve eloquent cortex identification. We compared alpha, beta and broadband gamma activity, and their combination for the identification of eloquent cortical areas defined by ESM. Ten patients participated in a delayed-match-to-sample task, where syllable sounds were matched to visually presented letters and responses given by keyboard. We used a generalized linear model (GLM) approach to find the optimal weighting of low frequency bands and broadband gamma power to predict the ESM categories. Broadband gamma activity increased more in eloquent areas than in non-eloquent areas and this difference had a diagnostic ability (area under (AU) the receiving operating characteristic curve - AUROC) of ∼70%. Both alpha and beta power decreased more in eloquent areas. Alpha power had lower AUROC than broadband gamma while beta had similar AUROC. AUROC was enhanced by the combination of alpha and broadband gamma (3% improvement) and by the combination of beta and broadband gamma (7% improvement) over the use of broadband gamma alone. Further analysis showed that the relative performance of broadband gamma and low frequency bands depended on multiple factors including the time period of the cognitive task, the location of the electrodes and the patient’s attention to the stimulus. However, the combination of beta band and broadband gamma always gave the best performance. We show how ECoG power modulation from cognitive testing periods can be used to map the probability of eloquence by ESM and how this probability can be used as an aid for optimal ESM planning. We conclude that low frequency power during cognitive testing can contribute to the identification of eloquent areas in patients with focal refractory epilepsy improving its precision but does not replace the need of ESM.HighlightsGamma, alpha and beta band activity has significant diagnostic ability to identify ESM defined eloquent cortical areas.We present a novel method to combine gamma and low frequency activity for enhanced identification.We quantify how identification is dependent on analysis time window, cortical function, and patient’s attentional engagement.With further development, this approach may offer an alternative to ESM mapping with reduced burden for patients.

Introduction Though seizures are a common complication after stroke, only little scientific evidence is available about the impact of epilepsy on cognitive functioning and quality of life in patients who have had a stroke. Therefore, we assessed these items in a case–control study. Methods We studied 36 patients with poststroke epilepsy (PSE) and 36 matched patients who have had a stroke without epilepsy using parts of the FePsy (the computerized visual searching task (CVST) for central information processing speed and a reaction time test), the mini-mental-state examination (MMSE), the EuroQol, the stroke-adapted Sickness Impact Profile questionnaire (SA-SIP-30), the Barthel index, the modified Rankin scale, and the National Institutes of Health stroke scale (NIHSS). Results Patients with PSE had significantly lower scores on the CVST and MMSE. Generic quality of life was the same in patients with poststroke epilepsy and patients with stroke only, however, the SA-SIP-30 showed a lower disease-specific quality of life in patients with poststroke epilepsy. The Barthel index showed no difference between both groups, but both the modified Rankin scale and the NIHSS were significantly higher in patients with poststroke epilepsy, indicating more disability and neurological impairment in patients with PSE. Conclusions We found that PSE relates to impaired cognitive functioning, a lower disease-specific quality of life and more disability and neurological impairment. This underlines the importance of further clinical research in this field. This article is part of the Special Issue “Seizures & Stroke”

Objective: Epileptic seizures are a common complication after stroke. The relation between occurrence of seizures after stroke and long-term mortality remains elusive. We aimed to assess whether seizures in an early or late phase after ischemic stroke are an independent determinant of long-term mortality. Methods: We prospectively included and followed 444 ischemic stroke patients with a first-ever supratentorial brain infarct for at least 2 years after their stroke regarding the occurrence of seizures. The final follow-up for mortality is from April 2015 (follow-up duration 24.5–27.8 years, mean 26.0 years, SD 0.9 years). We compared patients with early-onset seizures with all seizure-free patients, whereas the patients with late-onset seizures were compared with the 1-week survivors without any seizures. We used Cox-regression analyses to correct for possible confounding factors. Results: Kaplan–Meier analysis showed significantly higher mortality for the patients with early-onset seizures (p = 0.002) but after correction for known risk factors for (long term) mortality early-onset seizures had no independent influence on long-term mortality (HR 1.09; 95% CI 0.64–1.85). In patients with late-onset seizures, no significant influence from late-onset seizures on long-term mortality was found (univariate p = 0.717; multivariate HR 0.81; 95% CI 0.54–1.20). Conclusion: Both early-onset and late-onset seizures do not influence long-term mortality after ischemic stroke.

Objective: Antiglutamate decarboxylase (anti-GAD) antibodies are associated with several neurological manifestations, like epilepsy and movement disorders. However, in daily neurological practice, it remains hard to define when to test for anti-GAD antibodies in patients with neurologic and/or psychiatric symptoms. Therefore, here, we report the patient characteristics of a large retrospective cohort of patients tested for anti-GAD antibodies in clinical practice and compare the characteristics of anti-GAD positive and anti-GAD negative patients.Methods: We blindly assessed relevant clinical symptoms and comorbidities and functional outcome with the modified Rankin Scale (mRS) in a retrospective observational cohort of all patients in which the decision to assess anti-GAD levels had been made based solely on the presence of possible associated neurological and/or psychiatric symptoms (N = 119).Results: Out of 119 patients, 17 (143%) were anti-GAD positive. The anti-GAD positive patients had a median age of 30 years (range: 3-64; 2 children). They all had epilepsy, with 8 (47%) patients reporting cognitive complaints. Psychiatric symptoms were less prevalent in anti-GAD positive patients, only 1 anti-GAD positive patient (6%) versus 34 anti-GAD negative patients (33%) reported psychiatric symptoms (p = 0.021). The most frequent comorbidity of anti-GAD positive patients was diabetes mellitus type 1 (n = 8). Twelve (71%) and 13 (78%) of the anti-GAD positive patients were functionally independent at the time of diagnosis and after one year, respectively (mRS score: 0 to 2). There was no significant difference in functional status at any time during follow-up compared with the anti-GAD negative group.Conclusion: Antiglutamate decarboxylase (anti-GAD) antibodies relate to epilepsy with or without cognitive complaints. However, psychiatric symptoms were almost absent in anti-GAD positive patients, and the presence of anti-GAD antibodies contributed little to the prognosis in our cohort. (C) 2018 Elsevier Inc. All rights reserved.

Introduction The Racine scale is a 5-point seizure behavior scoring paradigm used in the amygdala kindled rat. Though this scale has been applied widely in experimental epilepsy research, studies of reproducibility are rare. The aim of the current study was, therefore, to assess its interobserver variability and intraobserver variability. Material and methods A video database set was acquired in the course of amygdala kindling of 67 Wistar rats. Six blinded observers received scoring instructions and then viewed a set of 15 random videos (session #1). Next, each observer scored 379 to 1048 additional videos (session #2) and finally scored the same set of 15 videos again (session #3). Scores included the occurrence of seizures (yes or no), the total seizure time (start of stimulus until the absence of seizure behavior), and the highest Racine stage. Interobserver variability and intraobserver variability were assessed in and between sessions #1 and #3 using a 2-way mixed intraclass correlation or Cohen's kappa depending on the variable. Results Interobserver agreement in session #1 was 0.664 for seizure occurrence, 0.861 for total seizure time, and 0.797 for the highest Racine stage. In session #3, interobserver agreement on seizure occurrence declined to 0.492, total seizure time declined to 0.625, and agreement for the highest Racine stage was 0.725. Interobserver agreement was scored insufficiently on focal R2 seizures in both sessions (0.287 and 0.182). Intraobserver agreement reached > 0.80 agreement for seizure occurrence, highest seizure score, and total seizure time in 3 out of 4 observers. Racine's scale stage 2 seizure scores were only 0.135 in one observer but 0.650, 0.810, and 0.635 in the other observers. Discussion and conclusion Overall, interobserver agreement and intraobserver agreement in scoring with Racine's scale were adequate. However, because interobserver agreement declined after a period of individually scoring videos, we suggest periodic repetition of the standardized instruction in the course of evaluating videos in order to ensure reproducible results.

IntroductionEffective treatment of new-onset headache after craniotomy, especially anterior temporal lobectomy (ATL) and amygdalohippocampectomy for drug-resistant temporal lobe epilepsy, is a challenge. The current practice, acetaminophen combined with opioids is often reported by patients as insufficient and sometimes accompanied by opioid-related adverse effects. Based on expert opinion, anaesthesiologists therefore frequently consider s-ketamine as add-on therapy. This randomised parallel group design trial compares s-ketamine with a placebo as add on medication to a multimodal pain approach.Methods and analysisIn total 62 adult participants, undergoing ATL for drug resistant epilepsy under general anaesthesia, will be randomised to either receive a 0.25 mg/kg bolus followed by a continuous infusion of 0.1 mg/kg/hour of s-ketamine or placebo (0.9% NaCl) starting before incision and continued for 48 hours as an addition to acetaminophen and opioids administered in a patient-controlled analgesia pump. The primary outcome measure is the cumulative postoperative opioid consumption. Patient recruitment started August 2018 and will end in 2021. Secondary outcome measures are postoperative pain intensity scores, psychological parameters, length of hospital stay and adverse events and will be reassessed at 3 and 6 months after surgery, with a baseline measurement preoperatively. All data are collected by researchers who are blinded to the treatment. The data will be analysed by multivariable linear mixed-effects regression.Ethics and disseminationEthical approval has been given by the local medical ethical committee (NL61666.068.17). This study will be conducted in accordance with the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results of this trial will be publicly disclosed and submitted for publication in an international peer-reviewed scientific journal.Trial registration numberNTR6480.

Background and Purpose— Asymptomatic lacunar infarcts, white matter lesions, cerebral microbleeds, and enlarged perivascular spaces are MRI markers of cerebral small vessel disease (cSVD). Higher blood pressure (BP) levels are associated with the presence of these markers separately, but the association with the total burden of cSVD on brain MRI, expressed by the simultaneous presence of multiple markers of cSVD (a compound score), has not been investigated. Methods— We performed 24-hour ambulatory BP monitoring in 122 patients with first-ever lacunar stroke. On brain MRI, we scored the presence of each marker of cSVD. One point was awarded for the presence of each marker, producing a score between 0 and 4. Associations with BP levels were tested with ordinal regression analyses. Results— Eighteen (15%) patients had no markers of cSVD, and 6 (5%) patients had 4 markers. Most patients (45; 37%) had 2 different markers. After correction for age and sex, higher 24-hour, day, and night systolic (24-hour odds ratio, 1.25; 95% confidence interval, 1.02–1.52 per 10 mm Hg) and diastolic (24-hour odds ratio, 1.32; 95% confidence interval, 1.12–1.56 per 5 mm Hg) BP were all significantly associated with an increasing total burden of cSVD. Conclusions— We found a positive association of ambulatory BP levels with total burden of cSVD on brain MRI. With increasing BP levels, there is a piling up of damage in the brain. We suggest that further cSVD studies also consider viewing the total burden in addition to each of the MRI markers separately.

Enlarged Virchow-Robin spaces (EVRS) are considered to be a sign of cerebral small vessel disease. Hypertension is an important risk factor for cerebral small vessel disease, whereas ambulatory blood pressure (BP) is the strongest predictor of hypertension-related brain damage. However, the association between ambulatory BP levels and EVRS has never been investigated. The aim of this study was to determine the association between ambulatory BP levels and EVRS. In 143 first-ever lacunar stroke patients, we performed 24-h ambulatory BP monitoring after the acute stroke phase. On brain MRI we counted EVRS in the basal ganglia and the centrum semiovale. We graded the number of EVRS at each level into a three-category severity scale. We assessed the association between BP levels and EVRS by ordinal regression analysis. After adjusting for age, sex, extensive white matter lesions, and asymptomatic lacunar infarcts, higher day systolic (OR 1.21; 95 % CI 1.00-1.46 per 10 mmHg), day diastolic (1.18; 95 % CI 1.02-1.37 per 5 mmHg) and 24-h diastolic (OR 1.18; 95 % CI 1.01-1.37 per 5 mmHg) ambulatory BP levels were associated with EVRS at the basal ganglia level. No relation was found between ambulatory BP levels and EVRS in the centrum semiovale. Higher day ambulatory BP levels are associated with EVRS in the basal ganglia. This association was independent of the presence of extensive white matter lesions and asymptomatic lacunar infarcts. Our results imply that basal ganglia EVRS should be regarded as a separate manifestation of BP-related brain damage.

Objectives: New insights in the pathophysiology of lacunar stroke (LS) suggest that it is caused by increased permeability of the blood-brain barrier due to endothelial activation. Because endothelial cells are the major production and storage site of tissue factor pathway inhibitor (TFPI), this protein can be used as marker of endothelial activation. In this observational study we measured the different pools of TFPI, as a marker of endothelial function, in first-ever lacunar stroke patients. Methods: We determined antigen levels of total and free full-length (FL) TFPI using ELISA in 149 patients and 42 controls. Heparin-releasable free FL TFPI was determined in a random subset of 17 patients and 15 controls. By brain MRI, we classified LS patients as having isolated lacunar infarct (ILA) or silent ischemic lesions (SILs). Results: Plasma levels of total TFPI were highest in patients with SILs compared with those with ILA, but this association disappeared after correction for age and levels of low-density lipoprotein cholesterol. However, levels of heparin-releasable free FL TFPI were higher in patients than in controls. Conclusions: Although ambient plasma levels of total TFPI were not different in subtypes of LS, the increased levels of heparin-releasable TFPI in patients suggest a role of endothelial activation in the pathogenesis of LS. Neurology (R) 2012;78:493-498

Background and Purpose— Cerebral small vessel disease (CSVD) may be caused by endothelial dysfunction, whereas endothelial progenitor cells (EPC) may attenuate endothelial dysfunction. Their vitality is lower in CSVD. A subset of lymphocytes, angiogenic T-cells, is capable to stimulate EPC function. The purpose of our study was to explore the relation between CSVD manifestations, angiogenic T-cells, and EPC in hypertensive patients with CSVD. Methods— We compared 32 essential hypertensive patients with CSVD (white matter lesions, asymptomatic lacunar infarcts, or microbleeds on 1.5-Tesla MRI) to 29 age-matched and sex-matched hypertensive controls. We counted angiogenic T-cells (CD3 + /CD31 + /CD184 + ) and putative EPC (CD31 + /CD34 + /CD45 - /KDR + ) by flow cytometry and determined EPC vitality by in vitro cluster formation. Results— Putative EPC numbers were lower in hypertensive individuals with CSVD than in those without (10±7 . 10 3 /mL versus 13±6 . 10 3 /mL [median±interquartile range]; P =0.011). Angiogenic T-cell numbers were also lower in hypertensive individuals with CSVD than in those without (0.56±0.25 . 10 9 /mL versus 0.78±0.50 . 10 9 /mL; P =0.008). Higher angiogenic T-cell numbers independently related to absence of CSVD (odds ratio, 0.088; 95% confidence interval, 0.012–0.627). Conclusions— Our data suggest that angiogenic T-cells and putative EPC independently relate to radiological CSVD manifestations in hypertensive patients.

Background and Purpose— Results from case-control and case-case studies indicate that a positive family history of stroke (FHstroke) is an independent risk factor for lacunar stroke. Different lacunar stroke phenotypes can be distinguished on the basis of the presence of asymptomatic lacunar infarcts (aLACs), ischemic white-matter lesions, or brain microbleeds. The aim of the present study was to determine whether familial aggregation of stroke was different for lacunar stroke phenotypes. Methods— In 157 patients with a first-ever lacunar stroke, a complete first-degree FHstroke was obtained by a standardized questionnaire and additional interview. Lacunar stroke patients were categorized successively into groups, depending on the presence of aLACs, ischemic white-matter lesions, and brain microbleeds on magnetic resonance imaging. Results— Fifty-two percent of patients reported a positive FHstroke in at least one of their first-degree relatives. In younger (P Conclusions— A family history of stroke might be an independent risk factor for the lacunar stroke phenotype with aLACs at younger ages, suggesting a role for genetic factors in this phenotype caused by diffuse vasculopathy.

Background: Metabolic syndrome (MetS) is a cluster of three or more of the following risk factors: obesity, elevated blood pressure, elevated triglyceride level, elevated glucose level, and low high-density lipoprotein level. Lacunar infarcts (LS) account for 25% of all ischemic strokes and are small, deeply located brain infarcts. Two different subtypes exist, which are distinguished by the presence of concomitant white matter lesions (WML) on brain imaging. We determined the prevalence of MetS in LS and the association between MetS with LS subtypes in a series of first-ever LS patients. Methods: We included 92 patients with a first-ever LS, and 92 patients with a first-ever atheroslerotic cortical stroke (CS) matched for age and sex. LS subtypes were defined according to presence of concomitant WML. We defined MetS retrospectively according to previously defined standards. Results: 35.9% of LS patients and 45.7% of CS patients had MetS (OR 0.67; 95% CI 0.37–1.20). MetS was more prevalent in LS without WML than in LS with WML (44.4 and 23.7%, respectively; OR 2.98; 95% CI 1.04–8.47). Similarly, MetS related more to CS compared to LS with WML (OR 2.56; 95% CI 1.03–6.37). Conclusion: MetS relates more strongly to LS without WML and to CS, than to LS with WML. Our results suggest a different underlying mechanism between LS without WML and CS, and lacunar stroke with WML.

Background and Purpose— Hypertension is an important risk factor for brain microbleeds (BMBs) in lacunar stroke patients. However, beyond the qualitative label “hypertension,” little is known about the association with ambulatory blood pressure (BP) levels. Methods— In 123 first-ever lacunar stroke patients we performed 24-hour ambulatory BP monitoring after the acute stroke-phase. We counted BMBs on T2*-weighted gradient-echo MR images. Because a different etiology for BMBs according to location has been suggested, we distinguished between BMBs in deep and lobar location. Results— BMBs were seen in 36 (29.3%) patients. After adjusting for age, sex, number of antihypertensive drugs, asymptomatic lacunar infarcts, and white matter lesions, we found 24-hour, day, and night systolic and diastolic BP levels to be significantly associated with the presence and number of BMBs (odds ratios 1.6 to 2.3 per standard deviation increase in BP). Distinguishing between different locations, various BP characteristics were significantly associated with the presence of deep (or combined deep and lobar) BMBs, but not with purely lobar BMBs. Conclusions— Our results underline the role of a high 24-hour BP load as an important risk factor for BMBs. The association of BP levels with deep but not purely lobar BMBs is in line with the idea that different vasculopathies might be involved. Deep BMBs may be a particular marker of BP-related small vessel disease, but longitudinal and larger studies are now warranted to substantiate these findings.

Background and Purpose— Blood–brain barrier dysfunction may be an early phenomenon in the development of the small vessel disease, which underlies white matter lesions. Because vitamin B12 plays a role in maintaining the integrity of the blood–brain barrier, we studied serum vitamin B12 level in relation to such lesions. Methods— In 124 patients with first lacunar stroke, we measured serum vitamin B12 level and rated the degree of white matter lesions on MRI. Results— Mean vitamin B12 level was 202 pmol/L (SD, 68.9). Thirty-nine patients (31.5%) had a vitamin B12 level less than the lower reference value of 150 pmol/L. Lower vitamin B12 level was (statistically significant) associated with more severe periventricular white matter lesions (odds ratio/100 pmol/L decrease, 1.773; 95% CI, 1.001–3.003), but not with deep white matter lesions (odds ratio/100 pmol/L decrease, 1.441; 95% CI, 0.881–2.358; ordered multivariate regression analysis). Conclusions— More severe periventricular white matter lesions in lacunar stroke patients relate to lower vitamin B12 levels. A possible causal relationship should now be studied prospectively.

Cerebral small vessel disease results in silent ischemic lesions (SIL) among which is leukoaraiosis. In this process, endothelial damage is probably involved. Endothelial progenitor cells (EPC), are involved in endothelial repair. By restoring the damaged endothelium, EPC could mitigate SIL and cerebral small vessel disease. Haptoglobin 1-1, one of three phenotypes of haptoglobin, relates to SIL and may therefore attenuate the endothelial repair by EPC. Our aim was to quantify EPC number and function and to assess haptoglobin phenotype and its effect on EPC function in patients with a high prevalence of SIL: lacunar stroke patients. We assessed EPC In 42 lacunar stroke patients and 18 controls by flow cytometry and culture with fetal calf serum, patient and control serum. We determined haptoglobin phenotype and cultured EPC with the three different haptoglobin phenotypes. We found that EPC cluster counts were lower in patients (96.9 clusters/well +/- 83.4 (mean +/- SD)), especially in those with SIL (85.0 +/- 64.3), than in controls (174.4 +/- 112.2). Cluster formation was inhibited by patient serum, especially by SIL patient serum, but not by control serum. Patients with haptoglobin 1-1 had less clusters in culture, and when haptoglobin 1-1 was added to EPC cultures, cluster numbers were lower than with the other haptoglobin phenotypes. We conclude that lacunar stroke patients, especially those with SIL, have impaired EPC cluster formation, which may point at decreased endothelial repair potential. The haptoglobin 1-1 phenotype is likely a causative factor in this impairment.

Haptoglobin (Hp) 2-2 phenotype has been associated with peripheral and coronary artery disease and risk of vascular complications in diabetic patients, but any association of Hp polymorphism with cerebrovascular disease has not been explored so far. We aimed to study Hp polymorphism in a sample of 124 patients with a rather homogeneous type of cerebrovascular disease, namely first symptomatic lacunar stroke due to small vessel disease, in comparison with a large (n=918) control group. Hp phenotypes were determined using starch gel electrophoresis. Hp1 allele frequency was significantly higher in patients than in controls (0.480 vs. 0.395, p < 0.05), mainly due to a lower Hp2-2 phenotype frequency (25.0 vs. 36.3 %; OR 0.59; 95%CI 0.38-0.90; p < 0.05). This was even more pronounced in younger (60 years) patients (Hp1 allele frequency 0.539). Concomitant asymptomatic lacunar lesions were present in 82 patients, extensive white matter lesions in 47 patients. The association between Hp1 and lacunar stroke suggests that Hp may serve different functions depending on the pathological processes in various types of vascular disease in different organs. The association between Hp1 and lacunar stroke may relate to blood-brain barrier dysfunction, to the association between hypertension and cerebral small vessel disease, or a special dependence of small vessel wall integrity on Hp2-2 related angiogenic potential. The presence of concomitant signs of cerebral small vessel disease weakened the association between Hp1 and lacunar stroke, which could reflect a difference in underlying vascular pathophysiology in which Hp phenotype may play a different role.

Background and Purpose— Stroke is the leading cause of disability in the Western world; however, few therapies are at hand to decrease this burden. Summary of Review— Endothelial progenitor cells (EPCs) have been introduced in cardiovascular medicine as factotums. EPCs can repair damaged endothelium and attenuate the development and progression of atherosclerosis. Also, EPCs can form new vessels in ischemic areas and thus promote recovery after ischemic events. In stroke, however, EPC research is limited. In our overview, we provide background information on EPC use as a risk marker and as a potential therapeutic agent. Conclusion— In our opinion, the lack of EPC studies in stroke should instigate vascular neurologists to participate in EPC research, as EPCs could also change pathophysiological concepts and improve clinical treatments in vascular neurology.

Seizures are a common complication after an intracerebral hemorrhage (ICH) and the epilepsy might even be drug resistant. It is not known which factors determine the treatment response in post-ICH epilepsy. We included ICH patients retrospectively who survived at least the first 7 days, in the period from 2004 to 2009 and assessed seizure occurrence up to May 2013. We defined early seizures (ES) as seizures occurring within the first 7 days after the ICH, and late seizures (LS) as seizures occurring later than 7 days after the ICH. We defined drug-resistant epilepsy as a non-response to two adequately chosen and dosed drug regimens. In 857 patients surviving at least 7 days after ICH 69 (8.1 %), patients developed ES whereas LS occurred in 84 (9.8 %) subjects. Patients with ES had higher odds to develop LS, as compared to patients without ES [OR 3.4; 95 % confidence interval (CI) 2.1–5.6]. Drug-resistant post-ICH epilepsy occurred in 19 patients (22.6 %). The most important independent risk factor was the occurrence of ES (OR 3.0; 95 %-CI 1.1–8.4). ES are the main independent risk factor for the development of LS and for the development of drug-resistant epilepsy. Thus, ES might hallmark the start of chronic epilepsy after intracerebral hemorrhage and are not to be considered of no significance.

BACKGROUND Hypertension is associated with the occurrence of cognitive deficits and dementia, probably because hypertension is a major risk factor for the occurrence of brain damage as a result of cerebral small vessel disease (cSVD). Endothelial activation and inflammation have been suggested to play an important role in the pathogenesis of cSVD. We investigated if compound scores of endothelial activation or inflammation, based on several blood markers, are associated with cognitive performance 3 years later in patients with essential hypertension. METHODS At baseline, levels of blood markers of endothelial activation (soluble vascular cellular adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), sP-selectin, and sE-selectin) and markers of inflammation (neopterin, C-reactive protein, and sICAM-1) were measured and transformed into compound scores using z-scores. In addition, a brain magnetic resonance imaging (MRI) was performed to determine the presence of cSVD-related MRI markers. Three years later, patients underwent a neuropsychological assessment to determine cognitive performance. RESULTS A total of 101 patients with hypertension were included in the present study. In multiple linear regression analyses with correction for demographics and MRI markers, the compound score of endothelial activation (B = -0.19, 95% confidence interval = -0.34 to -0.04, P = 0.014), but not of inflammation (B = -0.09, 95% confidence interval = -0.22 to 0.05, P = 0.198), was associated with worse cognitive performance. CONCLUSIONS Our results show that an overall measure of endothelial activation is associated with cognitive performance in patients with essential hypertension. This indicates that a process involving endothelial activation might play a role in the pathogenesis of cognitive problems in patients with hypertension.

BACKGROUND: Health care-related adverse events (HCRAEs), which should not be confused with (blameworthy) medical errors, are common; they can lead to hospital admissions and can have grave consequences. Although they are sometimes potentially preventable, information is lacking on HCRAEs leading to admission to different departments. AIM: This study aimed to gain insight into the incidence, type, severity, and preventability of HCRAEs (including adverse drug events) leading to hospitalization to the departments of internal medicine, surgery, orthopedics, neurology, and neurosurgery. Further, we explore if there are differences regarding these HCRAEs between these departments. METHODS: We retrospectively evaluated the medical records of all patients admitted through the emergency department (ED) in a 6-month period to the departments of internal medicine, surgery, orthopedics, neurology, and neurosurgery. All patients admitted because of HCRAEs were included. RESULTS: More than one-fifth (21.8%; range 12.0%-47.8%) of all admissions to the 5 departments were due to a HCRAE. Half (49.9%) of these HCRAEs were medication-related and 30.5% were procedure-related. In 6.5% of patients, the HCRAE led to permanent disability and another 4.4% of patients died during hospitalization. HCRAEs treated by internists and neurologists were usually medication-related, whereas HCRAEs treated by surgeons, orthopedic surgeons, and neurosurgeons were usually procedure-related. CONCLUSION: Hospital admissions to different departments are often caused by HCRAEs, which sometimes lead to permanent disability or even death. Gaining insight into similarities and differences in HCRAEs occurring in different specialties is a starting point for improving clinical outcomes.

Introduction: Patients with medically refractory epilepsy treated with deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) vary highly in their therapy response. Proper positioning of the DBS lead is crucial to maximize efficacy and minimize side effects. For a correct implantation, the ANT is anatomically located using pre-operative 3T MRI and perioperative microelectrode recordings (MER). Neurons in the ANT have highly variable, yet characteristic patterns of firing in bursts. During DBS lead implantation, we noted differences among patients’ characteristic burst patterns along the electrode trajectory. In this study, we investigate whether electrophysiological characteristics of the target region could predict therapy response to DBS and could thus be used to improve ANT targeting during DBS surgery. Objectives: To determine whether perioperative neurophysiological characteristics relate to therapy response in DBS for patients with medically refractory epilepsy. Patients and methods: We included ten consecutive epilepsy patients planned for DBS surgery at Maastricht University Medical Center. All patients were diagnosed with medically refractory epilepsy and had incapacitating seizures. Patients failed trials of at least two reasonably tolerated and adequately chosen antiepileptic drug schedules. Using pre-operative 3T MRI, we planned an extraventricular approach to target. The ANT was defined as a grey matter structure at the top of the mamillothalamic tract. Along this trajectory, we performed stereotactic single cell MERs. The anatomical location of the recordings were verified using preoperative 3T MR images. We compared characteristics of the neural signals at different depths along the trajectory between DBS responders and non-responders. Responders were defined as patients with a seizure frequency reduction of more than 50% at one year follow-up. Results: Using MER data from 19 electrode trajectories of ten patients (one unilateral and nine bilateral trajectories), we found high-amplitude neuronal bursts around the target area or ANT. Responders to DBS (n = 5) had higher normalized mean firing rates and mean burst rates near the target area compared to non-responders (n = 5), with a clearer delineation between the target region and surroundings. Electrode trajectories and lead localization did not differ between responders and non-responders. Conclusion: Single cell firing patterns in the ANT relate to therapy response in DBS for patients with medically refractory epilepsy. Analysis of single cell firing patterns using MER may guide targeting or contribute to predicting therapy response to ANT DBS. Further exploration into the use of electrophysiological recordings is warranted to improve targeting or predict outcome in DBS for epilepsy patients.

Background and Purpose— Elevated blood pressure (BP) is associated with the presence of cerebral microbleeds (CMBs) in cross-sectional studies. However, longitudinal studies did not show a convincing relationship. We aimed to determine the association between elevated BP levels and the occurrence of new CMBs after a 2-year follow-up in first-ever lacunar stroke patients using ambulatory BP monitoring. Methods— Ninety-six first-ever lacunar stroke patients underwent brain MRI and ambulatory BP monitoring at baseline and after 2-year follow-up. We used logistic regression analyses to assess the association of BP levels with new CMBs. Results— We found new CMBs in 17 patients (18%). Higher 24-hour, day and night systolic BP (odds ratio, 2.69; 95% confidence interval, 1.40–5.21 per SD increase for 24-hour BP) and diastolic BP (odds ratio, 2.13; 95% confidence interval, 1.15–3.90 per SD increase for 24-hour BP) at baseline were associated with the development of new CMBs independent of age and sex. BP levels decreased during follow-up in both patients with and without new CMBs. Unlike BP levels at baseline, there was no difference in BP levels at follow-up between patients with and without new CMBs. Conclusions— Both higher systolic and diastolic BP levels were associated with the development of new CMBs in a population of lacunar stroke patients. Decrease of BP levels during follow-up did not halt progression of CMBs; however, it remains to be determined whether (early) intervention with antihypertensive drugs can slow down progression of CMBs.

We read the review by Moore et al. (2012), recently published in this journal, with great interest and compliment the authors for their thorough review of cognitive impairment and its relation to vitamin B12.

Background Positive family history of stroke is an independent risk factor for lacunar stroke. However, the magnitude of familial aggregation of a certain disease is better evaluated by the genetic relative risk. This is calculated by dividing the prevalence of specific disease in family members of patients by the prevalence of this disease in the general population. In a cohort of lacunar stroke patients, who were subtyped clinically and radiologically, we determined the genetic relative risk of stroke. Methods By questionnaire and additional interview, we obtained a complete first-degree family history of stroke. The prevalence of stroke in first-degree relatives of these lacunar stroke patients was compared to the self-reported prevalence of stroke in a Dutch community based cohort of elderly volunteers. Secondly, the influence of proband characteristics and family composition on parental and sibling history of stroke were evaluated. Principal Findings We collected data of 1066 first-degree relatives of 195 lacunar stroke patients. Strokes occurred in 13.5% of first-degree relatives. The genetic relative risk was 2.94 (95%CI 2.45–3.53) for overall first-degree relatives, 4.52 (95%CI 3.61–5.65) for patients' parents and 2.10 (95%CI 1.63–2.69) for patients' siblings. Age of proband and proband status for hypertension influenced the chance of having a parent with a history of stroke whereas the likelihood of having a concordant sibling increased with sibship size. Conclusions We found an increased genetic relative risk of stroke in first-degree relatives of patients with lacunar stroke. Our data warrant further genomic research in this well-defined high risk population for stroke.

Cerebral small vessel disease (CSVD) is considered to be caused by an increased permeability of the blood-brain barrier and results in enlargement of Virchow Robin spaces (VRs), white matter lesions, brain microbleeds, and lacunar infarcts. The increased permeability of the blood-brain barrier may relate to endothelial cell activation and activated monocytes/macrophages. Therefore, we hypothesized that plasma markers of endothelial activation (adhesion molecules) and monocyte/macrophage activation (neopterin) relate to CSVD manifestations. In 163 first-ever lacunar stroke patients and 183 essential hypertensive patients, we assessed CSVD manifestations on brain magnetic resonance imaging (MRI) and levels of C-reactive protein (CRP), neopterin, as well as circulating soluble adhesion molecules (sICAM-1, sVCAM-1, sE-selectin, sP-selectin). Neopterin, sICAM-1 and sVCAM-1 levels were higher in patients with extensive CSVD manifestations than in those without (p < 0.01). Neopterin levels independently related to higher numbers of enlarged Virchow Robin spaces (p < 0.001). An inflammatory process with activated monocytes/macrophages may play a role in the increased permeability of the blood brain barrier in patients with CSVD.

Background and Purpose— Oxidized low-density lipoprotein (oxLDL) induces endothelial dysfunction and antibody formation. Because endothelial dysfunction is involved in cerebral small vessel disease (CSVD) (dilated Virchow Robin spaces, lacunar infarcts, and white matter lesions), oxLDL antibodies could play a role in CSVD pathogenesis. Therefore, we studied oxLDL antibodies in patients with high prevalence of CSVD: lacunar stroke patients and essential hypertensive patients. Methods— A total of 158 lacunar stroke patients, 158 hypertensive patients, and 43 healthy controls were included. We determined levels of IgG and IgM against hypochlorite (HOCl) and malondialdehyde (MDA) oxLDL using ELISA (values in optical density). Results— Patients with CSVD had higher levels of IgG-HOCl-oxLDL (0.77 versus 0.70; P P P Conclusions— An autoinflammatory process with lower levels of IgM antibodies and higher levels of IgG antibodies against oxLDL may be involved in CSVD.

Background and Purpose— Lacunar stroke (LS) can be subtyped according to the absence (isolated lacunar infarct [ILA]) or presence of concomitant white matter lesions (WML) and/or asymptomatic lacunar infarcts. Endothelial activation is thought to play a pivotal role in the subtype with WML and/or asymptomatic lacunar infarcts. The aim of this study was to evaluate whether endothelial activation is associated with WML and/or asymptomatic lacunar infarcts in LS patients. Here, we determined levels of circulating blood markers of endothelial function in LS patients. Methods— In 149 patients, all of whom had brain-MRI, levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), tPA–PAI-1 complex, von Willebrand factor, tissue factor, thrombomodulin, and coagulation factor VIII were determined. Levels of blood markers were related to subtypes of LS and adjusted for age, gender, and vascular risk factors. Results— In subtypes of LS, tPA activity was increased in patients with WML (0.79 IU/mL vs 0.44 IU/mL for ILA; P =0.02) and PAI-1-antigen levels were lowest in patients with WML (27.5 ng/mL vs 44.0 ng/mL for ILA; P =0.02). The association between WML and PAI-1 remained significant after multivariable analysis (OR, 0.99; 95% CI, 0.98–1.00 per ng/mL change of PAI-1; P =0.04). Conclusions— We found further evidence for the hypothesis of endothelial activation in the subtype of LS caused by a diffuse small vessel vasculopathy, as we found higher levels of tPA in patients with concomitant extensive WML than in those with ILA. Second, low levels of PAI-1 were associated with WML. We postulate that differences in activity of components of the fibrinolytic system might contribute to WML development.

Virchow-Robin spaces (VRs) are perivascular spaces surrounding the deep perforating brain arteries. VRs dilatation is pathologic, and it could be a manifestation of cerebral small vessel disease. In the present study we assessed the relation between VRs and silent ischemic lesions in a cohort of patients with cerebral small vessel disease. We divided dilated VRs on MRI (1.5 Tesla) into three semi-quantitative categories in 165 first ever lacunar stroke patients. We counted asymptomatic lacunar infarcts and graded white matter lesions, and compared the prevalence of vascular risk factors in different categories of VRs. We also determined independent predictors of silent ischemic lesions. VRs at basal ganglia level related to age, hypertension, asymptomatic lacunar infarcts, and white matter lesions. VRs at basal ganglia level predicted silent ischemic lesions (odds ratio 10.58 per higher VRs category; 95 %- confidence interval 3.40 – 32.92). Dilated VRs in the basal ganglia relate to the severity of cerebral small vessel disease and might be a manifestation of the same small vessel abnormality that causes silent ischemic lesions. This adds a role for VRs as a potential marker for small vessel disease.