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Background and Purpose- Left atrial enlargement has been shown to be associated with ischemic stroke, but the association with embolic stroke mechanisms remains unknown. We aim to study the associations between left atrial volume index (LAVI) and embolic stroke subtypes and atrial fibrillation (AF) detection on cardiac event monitoring in patients with embolic stroke of unknown source. Methods- Data were collected from a prospective cohort of consecutive patients with ischemic stroke admitted to a comprehensive stroke center over 18 months. Stroke subtype was classified into cardioembolic stroke, noncardioembolic stroke of determined mechanism (NCE), or embolic stroke of undetermined source (ESUS). Univariate and prespecified multivariable analyses were performed to assess associations between LAVI and stroke subtype and AF detection in patients with ESUS. Results- Of 1224 consecutive patients identified during the study period, 1020 (82.6%) underwent transthoracic echocardiography and had LAVI measurements. LAVI was greater in patients with cardioembolic stroke than NCE (41.4 mL/m²Â±18.0 versus 28.6 mL/m²Â±12.2; P<0.001) but not in ESUS versus NCE (28.9 mL/m²Â±12.6 versus 28.6 mL/m²Â±12.2; P=0.61). In multivariable logistic regression models, LAVI was greater in cardioembolic stroke versus NCE (adjusted odds ratio per mL/m², 1.07; 95% CI, 1.05-1.09; P<0.001) but not in ESUS versus NCE (adjusted odds ratio per mL/m², 1.00; 95% CI, 0.99-1.02; P=0.720). Among 99 patients with ESUS who underwent cardiac monitoring, 18.2% had AF detected; LAVI was independently associated with AF detection in ESUS (adjusted odds ratio per mL/m², 1.09; 95% CI, 1.02-1.15; P=0.007). Conclusions- LAVI is associated with cardioembolic stroke as well as AF detection in patients with ESUS, 2 subsets of ischemic stroke that benefit from anticoagulation therapy. Patients with increased LAVI may be a subgroup where anticoagulation may be tested for stroke prevention.

BACKGROUND:STRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti-JC virus (JCV) seronegative patients with early relapsing-remitting multiple sclerosis (RRMS). The objective of this prespecified 2-year interim analysis was to determine the effectiveness of natalizumab in establishing and maintaining no evidence of disease activity (NEDA) in early RRMS. METHODS:Patients aged 18-65 years had an RRMS diagnosis < 3 years prior to screening, an Expanded Disability Status Scale (EDSS) score ≤ 4.0, and anti-JCV antibody negative status. Magnetic resonance imaging was performed at baseline and yearly thereafter. Cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were evaluated at 2 years. NEDA (no 24-week-confirmed EDSS worsening, no relapses, no gadolinium-enhancing lesions, and no new/newly enlarging T2-hyperintense lesions) was evaluated over 2 years. The Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Score (MSIS-29) were assessed at baseline and 1 and 2 years. Statistical analysis used summary statistics and frequency distributions. RESULTS:The study population (N = 222) had early RRMS, with mean (standard deviation [SD]) time since diagnosis of 1.6 (0.77) years and mean (SD) baseline EDSS score of 2.0 (1.13). NEDA was achieved in 105 of 187 patients (56.1%) during year 1 and 120 of 163 (73.6%) during year 2. Over 2 years, 76 of 171 patients (44.4%) attained overall NEDA. Probabilities of 24-week-confirmed EDSS worsening and improvement were 14.1% and 28.4%, respectively. After 2 years, patients exhibited significant improvements from baseline in SDMT (n = 158; mean [SD]: 4.3 [11.8]; p < 0.001) and MSIS-29 physical (n = 153; mean [SD]: - 3.9 [14.7]; p = 0.001), psychological (n = 152; mean [SD]: - 2.0 [7.9]; p < 0.001), and quality-of-life (n = 153; mean [SD]: - 6.0 [21.3]; p < 0.001) scores. CONCLUSIONS:These results support natalizumab's effectiveness over 2 years, during which nearly half of early RRMS patients achieved NEDA. During year 2, nearly 75% of patients exhibited NEDA. Over 2 years, patients continued to experience significant cognitive and quality-of-life benefits. These results are limited by the lack of a comparator group to determine the extent of a placebo effect. TRIAL REGISTRATION/BACKGROUND:clinicaltrials.gov, NCT01485003 , registered 5 December 2011.

BACKGROUND:Migraine and epilepsy are comorbid conditions. While it is well known that epilepsy can have an impact on cognitive abilities, there is conflicting evidence in the literature on the relationship between migraine and cognitive function. The aim of this study was to assess whether migraine comorbidity in patients with newly diagnosed focal epilepsy is associated with cognitive dysfunction. METHODS:This is a post hoc analysis of data prospectively collected for the Human Epilepsy Project (HEP). There were 349 participants screened for migraine with the 13 questions used in the American Migraine Prevalence and Prevention (AMPP) study. Participants were also screened for depression using the Neurological Disorder Depression Inventory for Epilepsy (NDDI-E) and the Center for Epidemiologic Studies Depression Scale (CES-D) and for anxiety using the Generalized Anxiety Disorder-7 (GAD-7) scale. Cognitive performance was assessed with the Cogstate Brief Battery and Aldenkamp-Baker Neuropsychological Assessment Schedule (ABNAS). RESULTS:About a fifth (21.2%) of patients with a new diagnosis of focal epilepsy screened positive for migraine. There were more women and less participants employed full time among the participants with comorbid migraine. They reported slightly more depressive and anxious symptoms than the participants without migraine. Migraine comorbidity was associated with ABNAS memory score (median: 2, range: 0-12, Mann Whitney U p-value: 0.015). However, migraine comorbidity was not associated with Cogstate scores nor ABNAS total scores or other ABNAS domain scores. In linear regressions, depression and anxiety scores were associated with the ABNAS memory score. CONCLUSION/CONCLUSIONS:In this study, there was no association between migraine comorbidity and objective cognitive scores in patients with newly diagnosed focal epilepsy. The relationship between migraine comorbidity and subjective memory deficits seemed to be mediated by the higher prevalence of depression and anxiety symptoms in patients with epilepsy with comorbid migraine.

Magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE) may be a distinct syndrome from TLE with mesial temporal sclerosis (TLE-MTS). Imaging and neuropsychological features of TLE-MTS are well-known; yet, these features are only beginning to be described in MRI-negative TLE. This study examined whether a quantitative measure of cortical gray and white matter blurring (GWB) was elevated in the temporal lobes ipsilateral to the seizure onset zone of individuals with MRI-negative TLE relative to TLE-MTS and healthy controls (HCs) and whether GWB elevations were associated with neuropsychological comorbidity. Gray-white matter blurring from 34 cortical regions and hippocampal volumes were quantified and compared across 28 people with MRI-negative TLE, 15 people with TLE-MTS, and 51 HCs. Declarative memory was assessed with standard neuropsychological tests and the intracarotid amobarbital procedure (IAP). In the group with MRI-negative TLE (left and right onsets combined), hippocampal volumes were within normal range but GWB was elevated, relative to HCs, across several mesial and lateral temporal lobe regions ipsilateral to the seizure onset zone. Gray-white matter blurring did not differ between the groups with TLE-MTS and HC or between the groups with TLE-MTS and MRI-negative TLE. The group with MRI-negative TLE could not be distinguished from the group with TLE-MTS on any of the standard neuropsychological tests; however, ipsilateral hippocampal volumes and IAP memory scores were lower in the group with TLE-MTS than in the group with MRI-negative TLE. The group with left MRI-negative TLE had lower general cognitive abilities and verbal fluency relative to the HC group, which adds to the characterization of neuropsychological comorbidities in left MRI-negative TLE. In addition, ipsilateral IAP memory performance was reduced relative to contralateral memory performance in MRI-negative TLE, indicating some degree of ipsilateral memory dysfunction. There was no relationship between hippocampal volume and IAP memory scores in MRI-negative TLE; however, decreased ipsilateral IAP memory scores were correlated with elevated GWB in the ipsilateral superior temporal sulcus of people with left MRI-negative TLE. In sum, GWB elevations in the ipsilateral temporal lobe of people with MRI-negative TLE suggest that GWB may serve as a marker for reduced structural integrity in regions in or near the seizure onset zone. Although mesial temporal abnormalities might be the major driver of memory dysfunction in TLE-MTS, a loss of structural integrity in lateral temporal lobe regions may contribute to IAP memory dysfunction in MRI-negative TLE.

The protein superoxide dismutase 1 (SOD1) is a copper and zinc-binding protein that has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). The Zn(II) binding to SOD1 is critical for the stability of the protein, and has been by itself implicated in ALS pathogenesis. Hence, the quantum mechanical (QM) study of the Zn(II)-site of SOD1 is relevant for understanding ALS. The hybrid QM-molecular mechanics (QM/MM) approach commonly employed for the QM study of proteins is highly dependent on the size of the sub-system treated quantum-mechanically. The size of the QM system also determines the computational feasibility of a given method. In the present work, we compare optimized geometries for the metal site and Zn(II) dissociation energies obtained with a QM/MM methodology employing different sizes for the QM sub-system. We find that geometries converge rapidly to RMSDs of around 0.3 Å, and fails to converge further, while a QM system of 480 atoms was required for converging the Zn(II) interaction energy of SOD1 to within 5 kcal*mol^-1, and a 611-atoms QM system for a 1 kcal*mol^-1 convergence with respect to our reference, 1280 QM-atoms system. Graphical Abstract The size of the QM system is critical for both the accuracy and the computational cost of a QM/MM calculation. We have identified a optimum balance for the study of the active site of the coppper, zinc superoxide dismutase.

In our first paper in this series (Epilepsia 2015; 56(5): 674-681), we published recommendations for the indications and expectations for neuropsychological assessment in routine epilepsy care. This partner paper provides a comprehensive overview of the more specialist role of neuropsychological assessment in the pre and postoperative evaluation of epilepsy surgery patients. The paper is in two parts. The first part presents the framework for the mandatory role of neuropsychologists in the presurgical evaluation of epilepsy surgery candidates. A preoperative neuropsychological assessment should be comprised of standardised measures of cognitive function in addition to wider measures of behavioural and psychosocial function. The results from the presurgical assessment are used to: (1) establish a baseline against which change can be measured following surgery; (2) provide a collaborative contribution to seizure characterization, lateralization and localization; (3) provide evidence-based predictions of cognitive risk associated with the proposed surgery; and (4) provide the evidence base for comprehensive preoperative counselling, including exploration of patient expectations of surgical treatment. The second part examines the critical role of the neuropsychologist in the evaluation of postoperative outcomes. Neuropsychological changes following surgery are dynamic and a comprehensive, long-term assessment of these changes following surgery should form an integral part of the postoperative follow-up. The special considerations with respect to pre and postoperative assessment when working with paediatric populations and those with an intellectual disability are also discussed. The paper provides a summary checklist for neuropsychological involvement throughout the epilepsy surgery process, based on the recommendations discussed.

Acute intermittent porphyria (AIP) is an inborn error of heme biosynthesis due to the deficiency of hydroxymethylbilane synthase (HMBS) activity. Human AIP heterozygotes have episodic acute neurovisceral attacks that typically start after puberty, whereas patients with homozygous dominant AIP (HD-AIP) have early-onset chronic neurological impairment, including ataxia and psychomotor retardation. To investigate the dramatically different manifestations, knock-in mice with human HD-AIP missense mutations c.500G>A (p.Arg167Glu) or c.518_519GC>AG (p.Arg173Glu), designated R167Q or R173Q mice, respectively, were generated and compared with the previously established T1/T2 mice with ~30% residual HMBS activity and the heterozygous AIP phenotype. Homozygous R173Q mice were embryonic lethal, while R167Q homozygous mice (R167Q+/+) had ~5% of normal HMBS activity, constitutively elevated plasma and urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), profound early-onset ataxia, delayed motor development and markedly impaired rotarod performance. Central nervous system (CNS) histology was grossly intact, but CNS myelination was delayed and overall myelin volume was decreased. Heme concentrations in liver and brain were similar to those of T1/T2 mice. Notably, ALA and PBG concentrations in the cerebral spinal fluid and CNS regions were markedly elevated in R167Q+/+ mice compared with T1/T2 mice. When the T1/T2 mice were administered phenobarbital, ALA and PBG markedly accumulated in their liver and plasma, but not in the CNS, indicating that ALA and PBG do not readily cross the blood-brain barrier. Taken together, these studies suggest that the severe HD-AIP neurological phenotype results from decreased myelination and the accumulation of locally produced neurotoxic porphyrin precursors within the CNS.