Nikos Triantafyllou

Velocity Criteria for Intracranial Stenosis Revisited An International Multicenter Study of Transcranial Doppler and Digital Subtraction Angiography

Background and Purpose— Intracranial atherosclerotic disease is associated with a high risk of stroke recurrence. We aimed to determine accuracy of transcranial Doppler screening at laboratories that share the same standardized scanning protocol. Methods— Patients with symptoms of cerebral ischemia were prospectively studied. Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) criteria were used for identification of ≥50% stenosis. We determined velocity cutoffs for ≥70% stenosis on digital subtraction angiography by Warfarin–Aspirin Symptomatic Intracranial Disease criteria and evaluated novel stenotic/prestenotic ratio and low-velocity criteria. Results— A total of 102 patients with intracranial atherosclerotic disease (age 57±13 years; 72% men; median National Institutes of Health Stroke Scale 3, interquartile range 6) provided 690 transcranial Doppler/digital subtraction angiography vessel pairs. On digital subtraction angiography, ≥50% stenosis was found in 97 and ≥70% stenosis in 62 arteries. Predictive values for transcranial Doppler SONIA criteria were similar (P>0.9) between middle cerebral artery (sensitivity 78%, specificity 93%, positive predictive value 73%, negative predictive value 94%, and overall accuracy 90%) and vertebral artery/basilar artery (69%, 98%, 88%, 93%, and 92%). As a single velocity criterion, most sensitive mean flow velocity thresholds for ≥70% stenosis were: middle cerebral artery >120 cm/s (71%) and vertebral artery/basilar artery >110 cm/s (55%). Optimal combined criteria for ≥70% stenosis were: middle cerebral artery >120 cm/s, or stenotic/prestenotic ratio ≥3, or low velocity (sensitivity 91%, specificity 80%, receiver operating characteristic 0.858), and vertebral artery/basilar artery >110 cm/s or stenotic/prestenotic ratio ≥3 (60%, 95%, 0.769, respectively). Conclusions— At laboratories with a standardized scanning protocol, SONIA mean flow velocity criteria remain reliably predictive of ≥50% stenosis. Novel velocity/ratio criteria for ≥70% stenosis increased sensitivity and showed good agreement with invasive angiography.

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 (I2 = 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.

Effect of long-term valproate monotherapy on bone mineral density in adults with epilepsy

BACKGROUND We evaluated the cross-sectional relationship of duration and dosage of valproate monotherapy on bone mineral density (BMD) in adult patients with epilepsy. METHODS The BMD at lumbar level (L2-L4) was measured in consecutive adult epileptic patients receiving long-term (> or =2 years) valproate monotherapy by dual energy X-ray absorptiometry (DXA). Blood samples were collected for total serum calcium, phosphorus, magnesium, 25-hydroxyvitamin D(3) and parathormone. Osteopenia and osteoporosis were defined according to the World Health Organization operational BMD definition. Cross-sectional associations were evaluated using Spearmans correlation coefficient. RESULTS A total of 41 patients were studied (mean age 32.3+/-8.2 years, 12 men, mean duration of valproate monotherapy 10.6+/-7.4 years). Osteopenia was present in 24% of subjects, while no case of osteoporosis was documented. Duration and dosage of valproate monotherapy did not correlate with BMD. No association was documented between duration or dosage of valproate monotherapy and biochemical parameters. CONCLUSIONS Duration of valproate monotherapy does not correlate with decreased BMD in adult patients with epilepsy. No case of osteoporosis was identified in patients treated with valproate for a mean period of more than ten years. These findings indicate that bone metabolism may not be affected by valproate monotherapy.

Safety of transcranial Doppler ‘bubble study’ for identification of right to left shunts: an international multicentre study

Background and purpose A recent retrospective study using an online list service established by the American Academy of Neurology has suggested that ischaemic cerebrovascular events may occur in patients who undergo ‘bubble studies’ (BS) with either transcranial Doppler (TCD) or transoesophageal echocardiography (TOE). The safety of TCD-BS for right to left shunt (RLS) identification was evaluated prospectively in an international multicentre study. Methods Consecutive patients with cerebral ischaemia (ischaemic stroke or transient ischaemic attack (TIA)) were screened for potential ischaemic cerebrovascular events following injection of microbubbles during TCD-BS for identification of RLS at three tertiary care stroke centres. TCD-BS was performed according to the standardised International Consensus Protocol. TOE-BS was performed in selected cases for confirmation of TCD-BS. Results 508 patients hospitalised with acute cerebral ischaemia (mean age 46±12 years, 59% men; 63% ischaemic stroke, 37% TIA) were investigated with TCD-BS within 1 week of ictus. RLS was identified in 151 cases (30%). TOE-BS was performed in 101 out of 151 patients with RLS identified on TCD-BS (67%). It was positive in 99 patients (98%). The rate of ischaemic cerebrovascular complications during or after TCD-BS was 0% (95% CI by the adjusted Wald method: 0–0.6%). Structural cardiac abnormalities were identified in 38 patients, including atrial septal aneurysm (n=23), tetralogy of Fallot (n=1), intracardiac thrombus (n=2), ventricular septal defect (n=3) and atrial myxoma (n=1). Conclusion TCD-BS is a safe screening test for identification of RLS, independent of the presence of cardiac structural abnormalities.

Lack of association between vitamin D levels and bone mineral density in patients with multiple sclerosis

BACKGROUND There is conflicting evidence regarding the association of vitamin D status with bone mineral density (BMD) in adult patients with multiple sclerosis (MS). We evaluated cross-sectionaly the determinants (including vitamin D levels) of low BMD in patients with relapsing-remitting MS (RRMS). METHODS The BMD at lumbar level (L2-L4) and femoral neck was measured in consecutive adult, ambulatory, RRMS patients by dual-energy X-ray absorptiometry. Blood samples were collected for total serum calcium, phosphorus, magnesium, 25-hydroxyvitamin D(3) and parathormone. Osteopenia and osteoporosis were defined according to the World Health Organization operational BMD definition. MS severity was assessed using the EDSS-score. Cross-sectional associations were evaluated using Spearmans correlation-coefficient and multiple linear regression models. RESULTS A total of 119 patients were evaluated (mean age 39.2 ± 10.4 years; 40% men). Osteopenia at lumbar spine (L2-L4) and femoral neck was present in 26% (95%CI: 18%-35%) and 50% (95%CI: 41%-60%) of the patients respectively. Osteoporosis was documented at lumbar spine and femoral neck of 3% (95%CI: 0%-8%) and 11% (95%CI: 6%-18%) of the study population respectively. There was no correlation (p>0.1) of 25-hydroxyvitamin D3 levels with any of BMD measurements (including Z- and T-scores) both in lumbar spine and in femoral neck. Increasing MS duration and increasing dosage of intravenous corticosteroids were independently and negatively associated with both lumbar spine and femoral neck BMD. CONCLUSIONS We documented no correlation between vitamin D levels and decreased BMD at femoral neck and lumbar spine in RRMS patients. Vitamin D insufficiency appears not to be the underlying cause of secondary osteoporosis in MS.

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.

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 (I2 = 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 (I2 = 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.

Rivaroxaban presents a better pharmacokinetic profile than dabigatran in an obese non-diabetic stroke patient.

Novel oral anticoagulants (NOACs) are the recent therapeutic breakthrough in the thromboprophylaxis of non-valvular atrial fibrillation (NVAF). There are currently three different molecules approved for NVAF: dabigatran, rivaroxaban and apixaban. All three agents have demonstrated at least non-inferiority at major clinical endpoints compared to warfarin with their major advantage being the fixed-dose regimen that necessitates no regular blood tests and protects patients from the disastrous effects of infra-therapeutic (embolism) or supratherapeutic (hemorrhage) anticoagulation. VKAs have been notorious for their interindividual variability and intraindividual variability in attaining effective plasma concentrations as well as their frequent drug and food interactions that impose regular International Normalized Ratio (INR) and dose adjustments. The idea of a fixed-dose regimen anticoagulation that would apply to most patients (excluding those with renal insufficiency or concomitant treatment with specific drugs that influence NOAC levels) was warmly received by the clinicians worldwide with rapid endorsement of the new agents in clinical practice. It is generally accepted that, with the exception of emergency situations where the effect of NOACs on anticoagulation should be assessed, there is no place for NOAC level testing in everyday clinical practice. However, a non-diabetic patientweighing153kgwas reported to present an ischemic stroke despite treatment with dabigatran due to non-therapeutic drug levels [1]. We present the case of a 67-year-oldman that presentedwith ischemic stroke due to previously unknown NVAF. He was started on dabigatran 150 mg bid ten days post ictus. His weight was 124 kg and his height 177 cm (Body Mass Index 39.6 kg/m). Glycosylated hemoglobin was 5.8%. Creatinine clearance after 24-hour urine collection was 132 ml/min (normal range 80–120 ml/min). A week after treatment initiation we have tested dabigatran levels using the Hemoclot® thrombin inhibitor assay [2] before the morning dose, 2, 4 and 6 h after witnessed medication intake. We observed that the patient never reached the interquartile range for Cmax and was most of time below the interquartile range of Ctrough [3]. The patient was on bisoprolol and atorvastatin, neither of which has been shown to interact with dabigatran levels. We have substituted dabigatran with rivaroxaban 20 mg qd. Five days after treatment initiation, rivaroxaban concentrations measured with DiXal® Direct factor Xa Inhibitor [4] were found within the interquartile range for therapeutic peak and trough levels suggesting effective anticoagulation (Table 1). The safety of anticoagulation with NOACs has recently received increased attention in low-weight patients because of perceived fear of increased hemorrhagic complications but anticoagulation in obese patients remains a real-life therapeutic challenge in different anticoagulant treatments for various indications [5]. In a sub-group analysis of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study, dabigatran showed decreased trough concentrations with

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

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.