Structural MRI Correlates of Cognitive Event-Related Potentials in Multiple Sclerosis.

PURPOSE: Cognitive impairment in multiple sclerosis has been associated with cognitive event-related potentials and MRI abnormalities. This study aims to explore for the first time the association between P300 and MRI in multiple sclerosis. METHODS: Fifty-eight relapsing-remitting patients (41.5 ± 10.5 years old, 41 women, disease duration 139.7 ± 84.9 months) and 51 healthy controls were used. Visual P300 responses and a set of 2- or 3-dimensional MRI indices were obtained. Neuropsychological testing and psychological evaluations were also performed. RESULTS: Multiple sclerosis patients had significantly lower P300 amplitude and more prolonged P300 latencies and reaction times than healthy controls. In total, 67.2% of patients were identified with abnormal P300 response. These patients had greater disability and physical fatigue and had lower visuospatial memory scores than those with normal P300 response. Abnormally low P300 amplitude was associated with lower peripheral gray matter volume and was correlated only with normalized frontal horn width and normalized brain volume, after adjusting for age and education. The moderating role of brain reserve was also documented. CONCLUSIONS: P300 event-related potential was related to both linear and volumetric MRI markers. Future studies should expand these results in other disease types and longitudinally. Event-related potentials could serve as an ancillary tool for cognitive assessment in multiple sclerosis.

Structural MRI correlates of cognitive function in multiple sclerosis.

BACKGROUND: Cognitive impairment (CI) has been associated with numerous magnetic resonance imaging (MRI) indices in multiple sclerosis (MS) patients. In this study we investigated the association of a large set of 2D and 3D MRI markers with cognitive function in MS. METHODS: A sample of 61 RRMS patients (mean age 41.8 ± 10.6 years old, 44 women, mean disease duration 137.9 ± 83.9 months) along with 51 age and gender matched healthy controls was used in this cross-sectional study. Neuropsychological and other tests, along with a large set of 2D/3D MRI evaluations were made. RESULTS: 44.3% of patients had CI. CI patients had more disability, physical fatigue than non-CI patients and more psychological distress than non-CI patients and HCs. Also, CI patients had significantly larger third ventricle width and volume, smaller coprus callosum index and larger lesion volume than non-CI patients. These MRI markers also significantly predicted cognitive scores after adjusting for age and education, explaining about 30.6% of the variance of the total cognitive score. CONCLUSIONS: Selected linear and volumetric MRI indices predict cognitive function in MS. Future studies should expand these results by exploring longitudinal changes and producing normative data.

Statin Pretreatment and Microembolic Signals in Large Artery Atherosclerosis.

OBJECTIVE: Although statin pretreatment (SP) is associated with better outcomes in patients with acute cerebral ischemia after an ischemic stroke/transient ischemic attack, data on the underlying mechanism of this beneficial effect are limited. APPROACH AND RESULTS: We sought to evaluate the potential association between SP and microembolic signal (MES) burden in acute cerebral ischemia because of large artery atherosclerosis (LAA). We prospectively evaluated consecutive patients with first-ever acute cerebral ischemia because of LAA in 3 tertiary stroke centers over a 2-year period. All patients underwent continuous 1-hour transcranial Doppler monitoring of the relevant vessel at baseline (≤24 hours). SP was recorded and dichotomized as high dose or low-to-moderate dose. SP was documented in 43 (41%) of 106 LAA patients (mean age, 65.4±10.3 years; 72% men; low-to-moderate dose, 32%; high dose, 8%). There was a significant (P=0.022) dose-dependent effect between SP and MES prevalence: no SP (37%), SP with low-to-moderate dose (18%), and SP with high dose (0%). Similarly, a significant (P=0.045) dose-dependent effect was documented between SP and MES burden: no SP (1.1±1.8), SP with low-to-moderate dose (0.7±1.6), and SP with high dose (0±0). In multivariable logistic regression analysis adjusting for demographics, vascular risk factors, location of LAA, stroke severity, and other prevention therapies, SP was associated with lower likelihood of MES presence (odds ratio, 0.29; 95% confidence interval, 0.09-0.92; P=0.036). In addition, SP was found also to be independently related to higher odds of functional improvement (common odds ratio, 3.33; 95% confidence interval, 1.07-10.0; P=0.037). CONCLUSIONS: We found that SP in patients with acute LAA is related with reduced MES presence and lower MES burden with an apparently dose-dependent association.

Novel oral anticoagulants for the secondary prevention of cerebral ischemia: a network meta-analysis.

BACKGROUND: Novel oral anticoagulants (NOACs) have shown to be both safe and effective for ischemic stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). We conducted a network meta-analysis (NMA) using published data from secondary prevention subgroups of different phase III randomized clinical trials (RCTs) comparing individual NOACs with warfarin. METHODS: Eligible studies were identified by searching MEDLINE and SCOPUS and the Cochrane Central Register of Controlled Trials databases. First, we conducted a pairwise meta-analysis for each pairwise comparison, and then we performed NMA to combine direct and indirect evidence for any given pair of treatments. The comparative effects of all NOACs against warfarin were ranked with the surface under the cumulative ranking (SUCRA) curve for each outcome. RESULTS: We identified four RCTs (including 15,240 patients) comparing individual NOACs (apixaban, dabigatran, rivaroxaban) with warfarin. Using indirect evidence, dabigatran was related to a significantly lower risk of hemorrhagic stroke compared with rivaroxaban [risk ratio (RR) 0.28; 95% confidence interval (CI) 0.11-0.75], while rivaroxaban was associated with a significantly lower risk of major gastrointestinal bleeding compared with dabigatran (RR 0.14; 95% CI 0.03-0.74). We also performed clustered ranking plot for the primary efficacy and safety endpoints to identify the treatment with the probably best benefit-to-risk ratio profile. CONCLUSIONS: The three NOACs showed differences in terms of safety and efficacy for secondary stroke prevention in NVAF. Our findings can serve only as hypothesis generation and require independent confirmation in head-to-head RCTs, owing to the sparse available evidence and increased uncertainty in both indirect effect estimates and ranking of treatments.

The value of transesophageal echocardiography for embolic strokes of undetermined source.

OBJECTIVE: Our aim was to evaluate the diagnostic yield of transesophageal echocardiography (TEE) in consecutive patients with ischemic stroke (IS) fulfilling the diagnostic criteria of embolic strokes of undetermined source (ESUS). METHODS: We prospectively evaluated consecutive patients with acute IS satisfying ESUS criteria who underwent in-hospital TEE examination in 3 tertiary care stroke centers during a 12-month period. We also performed a systematic review and meta-analysis estimating the cumulative effect of TEE findings on therapeutic management for secondary stroke prevention among different IS subgroups. RESULTS: We identified 61 patients with ESUS who underwent investigation with TEE (mean age 44 ± 12 years, 49% men, median NIH Stroke Scale score = 5 points [interquartile range: 3-8]). TEE revealed additional findings in 52% (95% confidence interval [CI]: 40%-65%) of the study population. TEE findings changed management (initiation of anticoagulation therapy, administration of IV antibiotic therapy, and patent foramen ovale closure) in 10 (16% [95% CI: 9%-28%]) patients. The pooled rate of reported anticoagulation therapy attributed to abnormal TEE findings among 3,562 acute IS patients included in the meta-analysis (12 studies) was 8.7% (95% CI: 7.3%-10.4%). In subgroup analysis, the rates of initiation of anticoagulation therapy on the basis of TEE investigation did not differ (p = 0.315) among patients with cryptogenic stroke (6.9% [95% CI: 4.9%-9.6%]), ESUS (8.1% [95% CI: 3.4%-18.1%]), and IS (9.4% [95% CI: 7.5%-11.8%]). CONCLUSIONS: Abnormal TEE findings may decisively affect the selection of appropriate therapeutic strategy in approximately 1 of 7 patients with ESUS.

Case of Young-Onset Sporadic Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) constitutes the main type of motor neuron disease. Familial ALS is characterized by the presence of positive family history and accounts for 10% of ALS cases. Although familial ALS is the main culprit for early-onset disease, there are rare cases of early- or young-onset ALS with negative family history or sporadic ALS. We describe a 23-year-old man with clinical and electrophysiological evidence of probable sporadic ALS according to the revised EI Escorial criteria. Interestingly, brain neuroimaging revealed bilaterally increased T2 signals across corona radiata, posterior limb of the internal capsule, and descending motor tracts in the brainstem and hypointensity rim of the motor cortex on T2-weighted images. Young-onset sporadic ALS may be a distinct nosological entity. The topic is shortly discussed in the light of its genetic and clinical characteristics.

Brain Hyperechogenicities are not Associated with Venous Insufficiency in Multiple Sclerosis: A Pilot Neurosonology Study.

BACKGROUND AND PURPOSE: The "venous hypothesis" of multiple sclerosis (MS) postulates that intracranial venous congestion disintegrates the blood-brain barrier, resulting in iron accumulation in brain parenchyma triggering the inflammatory process of MS. Transcranial sonography (TCS) reveals brain parenchyma hyperechogenic alterations (BPHA) that are thought to reflect iron accumulation. We sought to investigate potential association of BPHA with chronic cerebrospinal venous insufficiency (CCSVI) in MS. METHODS: MS patients were evaluated according to established TCS protocol for extrapyramidal disorders examining the presence of hyperechogenicities in different basal ganglia regions. Cerebral and cervical venous system was assessed according to proposed ultrasound protocol for CCSVI detection. RESULTS: In a total of 32 MS patients (age = 40 ± 14 years; male = 41%; EDSS-score = 3.1 ± 2.2) brain parenchyma hyperechogenic alterations were detected in twelve (38%) patients. The two sonographers agreed independently in 28 (87.5%) of the 32 examinations, resulting in a substantial to almost perfect agreement (Cohen's weighted kappa: substantia nigra = 0.904, Lentiform nucleus = 0.871, Thalamus = 0.784, caudate nucleus = 0.651). Two (6%) patients fulfilled the neurosonology criteria of CCSVI, while in 7 patients (22%) one positive criterion was detected. No BPHA were observed in any MS patient fulfilling CCSVI criteria. The prevalence of one positive CCSVI feature did not differ (P = .999) among patients with present (25%) or absent (20%) BPHA. CONCLUSION: There was no association of BPHA with CCSVI findings. Our findings do not support the "venous hypothesis" resulting in iron accumulation even in the few MS patients fulfilling CCSVI-criteria.

The case for dosing dabigatran: how tailoring dose to patient renal function, weight and age could improve the benefit-risk ratio.

Dabigatran is increasingly being used in clinical practice for the thromboprophylaxis in atrial fibrillation as a convenient therapy that needs no drug level monitoring. However, analysis of the data of the same clinical trial that led to the adoption of dabigatran in fixed-dosing regimens has indicated a small subgroup of patients that could be either over-treated, risking bleeding, or under-treated, risking embolism. Additional post-marketing data lends support to the favorable therapeutic profile of dabigatran but at the same time raises doubts about patient characteristics such as weight, age, renal function and their pharmacokinetic effects that, in some cases, could be serious enough to expose a minority of patients to risk. We will present a clinical case of a patient with an ischemic stroke while on dabigatran that was found with low dabigatran plasma levels and we will discuss the currently available data on the effects of inherent patient characteristics on dabigatran pharmacokinetics, the clinical impact of dabigatran plasma levels on safety and efficacy as well as the possibility of improving the risk-benefit profile of this agent by tailoring the dose for selected patient groups.

A case of postmenopausal androgen excess.

Ovarian steroid cell tumors are very rare but potentially life-threatening neoplasms. They represent less than 0.1% of all ovarian tumors, typically present in premenopausal women and frequently manifest with virilization. Signs of hyperandrogenism may appear in postmenopausal women due to tumorοus and non-tumorοus adrenal and ovarian causes as well due to the normal aging process. In any case, steroid cell tumor should be suspected in postmenopausal women who present with rapid progressive androgen excess symptoms. This report describes a case of a 67-year-old postmenopausal woman with signs of hyperandrogenism, where an ovarian steroid cell tumor was diagnosed and treated by laparoscopic bilateral salpingo-oophorectomy and synchronous hysterectomy.

"Liberation treatment" for chronic cerebrospinal venous insufficiency in multiple sclerosis: the truth will set you free.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) has recently been introduced as a chronic state of impaired cerebral or cervical venous drainage that may be causally implicated in multiple sclerosis (MS) pathogenesis. Moreover, percutaneous transluminal angioplasty of extracranial veins termed "Liberation treatment" has been proposed (based on nonrandomized data) as an alternative therapy for MS. METHODS: A comprehensive literature search was conducted to identify available published, peer-reviewed, clinical studies evaluating (1) the association of CCSVI with MS, (2) the reproducibility of proposed ultrasound criteria for CCSVI detection (3) the safety and efficacy of "Liberation treatment" in open-label and randomized-controlled trial (RCT) settings. RESULTS: There is substantial heterogeneity between ultrasound case-control studies investigating the association of CCSVI and MS. The majority of independent investigators failed to reproduce the initially reported high prevalence rates of CCSVI in MS. The prevalence of extracranial venous stenoses evaluated by other neuroimaging modalities (contrast or MR venography) is similarly low in MS patients and healthy individuals. One small RCT failed to document any benefit in MS patients with CCSVI receiving "Liberation treatment", while an exacerbation of disease activity was observed. "Liberation treatment" has been complicated by serious adverse events (SAEs) in open-label studies (e.g., stroke, internal jugular vein thrombosis, stent migration, hydrocephalus). CONCLUSION: CCSVI appears to be a poorly reproducible and clinically irrelevant sonographic construct. "Liberation treatment" has no proven efficacy, may exacerbate underlying disease activity and has been complicated with SAEs. "Liberation treatment" should stop being offered to MS patients even in the settings of RCTs.

Intensive blood pressure reduction in acute intracerebral hemorrhage: a meta-analysis.

OBJECTIVE: The aim of the present systematic review and meta-analysis was to evaluate the safety and efficacy of intensive blood pressure (BP) reduction in patients with acute-onset intracerebral hemorrhage (ICH) using data from randomized controlled trials. METHODS: We conducted a systematic review and meta-analysis according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines of all available randomized controlled trials that randomized patients with acute ICH to either intensive or guideline BP-reduction protocols. RESULTS: We identified 4 eligible studies, including a total of 3,315 patients (mean age 63.4 ± 1.4 years, 64% men). Death rates were similar between patients randomized to intensive BP-lowering treatment and those receiving guideline BP-lowering treatment (odds ratio = 1.01, 95% confidence interval: 0.83-1.23; p = 0.914). Intensive BP-lowering treatment tended to be associated with lower 3-month death or dependency (modified Rankin Scale grades 3-6) compared with guideline treatment (odds ratio = 0.87, 95% confidence interval: 0.76-1.01; p = 0.062). No evidence of heterogeneity between estimates (I(2) = 0%; p = 0.723), or publication bias in the funnel plots (p = 0.993, Egger statistical test), was detected. Intensive BP reduction was also associated with a greater attenuation of absolute hematoma growth at 24 hours (standardized mean difference ± SE: -0.110 ± 0.053; p = 0.038). CONCLUSIONS: Our findings indicate that intensive BP management in patients with acute ICH is safe. Fewer intensively treated patients had unfavorable 3-month functional outcome although this finding did not reach significance. Moreover, intensive BP reduction appears to be associated with a greater attenuation of absolute hematoma growth at 24 hours.

Chronic cerebrospinal venous insufficiency and multiple sclerosis: a comprehensive meta-analysis of case-control studies.

OBJECTIVES: Chronic cerebrospinal venous insufficiency (CCSVI) has recently been implicated in the pathogenesis of multiple sclerosis (MS). This comprehensive meta-analysis of case-control studies investigates the association of CCSVI with MS. METHODS: Through Medline, EMBASE and Cochrane database searches, case-control ultrasound studies comparing CCSVI frequency among patients with MS and healthy controls were identified. RESULTS: We identified 19 eligible studies including 1250 patients with MS and 899 healthy controls. The pooled analysis showed that CCSVI was associated with MS [odds ratio (OR) 8.35; 95% confidence interval (CI) 3.44-20.31; p < 0.001) with considerable heterogeneity across studies (I (2) = 80.1%). This association was substantially attenuated in sensitivity analyses excluding studies that were carried out by the group that originally described CCSVI, included investigators who had also been involved in publications advocating endovascular procedures for CCSVI treatment, or were conducted in Italy. Our most conservative sensitivity analysis combining different exclusion criteria yielded no association of CCSVI with MS (OR 1.35; 95% CI 0.62-2.93; p = 0.453) without any heterogeneity (I (2) = 0%). CONCLUSION: There is considerable heterogeneity across different case-control studies evaluating the association of CCSVI and MS. The greatest factor contributing to this heterogeneity appears to be the involvement of investigators in other publications supporting endovascular procedures as a novel MS treatment.

Racial disparities in early mortality in 1,134 young patients with acute stroke.

We sought to investigate potential racial disparities in early outcomes of young individuals with stroke in an international multicenter study. We evaluated consecutive patients with first-ever acute stroke aged 18-45 years from prospective databases involving 12 tertiary-care stroke centers in North America (n = 2), Europe (n = 6), and Asia (n = 4). Demographics, vascular risk factors, stroke subtypes, pre-stroke functional status, stroke severity, blood pressure parameters, and serum glucose at hospital admission were documented. The outcome events of interest were 30-day mortality and 30-day favorable functional outcome (FFO) defined as modified-Rankin Scale score of 0-1. A total of 1,134 young adults (mean age 37.4 ± 7.0 years; 58.8 % men; 48.6 % Whites, 23.9 % Blacks, and 27.5 % Asians; median baseline National Institutes of Health Stroke Scale score 6 points, interquartile range 2-13) were included in the analyses. The 30-day stroke mortality and FFO rates differed (p < 0.001) across races. After adjusting for potential confounders, race was independently associated with 30-day mortality (p = 0.026) and 30-day FFO (p = 0.035). Blacks had a fourfold higher odds of 30-day stroke mortality in comparison to Asians (OR 4.00; 95 % CI 1.38-11.59; p = 0.011). Whites also had an increased likelihood of 30-day stroke mortality in comparison to Asians (OR 3.59; 95 % CI 1.28-10.03; p = 0.015). Blacks had a lower odds of 30-day FFO in comparison to Whites (OR 0.57; 95 % CI 0.35-0.91; p = 0.018). Racial disparities in early outcomes following first-ever stroke in young individuals appear to be independent of other known outcome predictor variables. Whites appear to have higher likelihood of 30-day FFO and Asians have lower odds of 30-day stroke mortality.

Teaching neuroimages: isolated sphenoiditis: an uncommon cause of abducens nerve palsy.

A 35-year-old woman presented with a headache lasting 2 weeks and complained of recent diplopia. Neurologic examination showed limited left eye abduction. Initial brain CT scan was considered normal (figure, A). Brain MRI showed left sphenoiditis (figure, B). The patient was treated with amoxicillin/clavulanic acid and corticosteroids with rapid symptom improvement which deferred endoscopy that could provide a bacteriologic diagnosis.