Pitchaiah Mandava

Hemorrhagic transformation of ischemic stroke in diabetics on sulfonylureas.

Disability or death occurs more frequently in patients with hemorrhagic transformation (HT) after ischemic stroke. In rat models of stroke, sulfonylurea (SU) drugs such as glibenclamide (adopted US name, glyburide) confer protection against swelling and HT through actions on the novel SUR1‐regulated NCCa‐ATP channel. Here, we sought to determine whether the use of SU drugs in patients with diabetes mellitus (DM) presenting with acute ischemic stroke might influence the incidence of HT.

Pilot Study of Intravenous Glyburide in Patients With a Large Ischemic Stroke

Background and Purpose— Preclinical and retrospective clinical data indicate that glyburide, a selective inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4, is effective in preventing edema and improving outcome after focal ischemia. We assessed the feasibility of recruiting and treating patients with severe stroke while obtaining preliminary information on the safety and tolerability of RP-1127 (glyburide for injection). Methods— We studied 10 patients with acute ischemic stroke, with baseline diffusion-weighted imaging lesion volumes of 82 to 210 cm3, whether treated with intravenous recombinant tissue-type plasminogen activator, age 18 to 80 years, and time to RP-1127 ⩽10 hours. Results— Recruitment was completed within 10 months. The mean age was 50.5 years, and baseline diffusion-weighted image lesion volume was 102±23 cm3. There were no serious adverse events related to drug and no symptomatic hypoglycemia. The increase in ipsilateral hemisphere volume was 50±33 cm3. The proportion of 90-day modified Rankin Scale ⩽4 was 90% (40% modified Rankin Scale, ⩽3). Conclusions— RP-1127 at a dose of 3 mg/d was well tolerated and did not require any dose reductions. A clinical trial of RP-1127 is feasible. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01268683.

Intra-arterial therapies for acute ischemic stroke

Background: There are no randomized trials comparing intra-arterial (IA) therapy with best medical treatment for acute ischemic stroke. To assess potential benefit from this therapeutic approach, we performed a systematic review of published IA series. Because outcome from stroke is highly dependent on baseline characteristics, we compared results against prognostic models adjusted for admission National Institute of Health Stroke Scale (NIHSS) scores and age. Methods: We selected articles from MEDLINE and Cochrane Databases based on specified criteria that included 3-month clinical follow-up. Outcome functions from prognostic models were generated and difference from prediction calculated for each study. Best and worst mortality performers were identified and assessed for factors that distinguished them. Results: We identified 27 reports with 30 treatment series representing 1,117 patients. Percent difference from predicted outcomes varied from −51 to +24.6% for mortality and −30.3 to +28.7% for good functional outcome. A mean overall difference in the percent that died compared with prediction was 0.25% (SD: ±3.5%; 95% CI: ±0.53) and in the percentage of those that achieved a good functional outcome compared with prediction was −0.15% (SD: ±2.7%; 95% CI: ±0.44). The quartile of better mortality performers relative to worst performers had a 4.8-point more severe NIHSS score at baseline (p = 0.028) and employed 50% lower doses of the most frequently used thrombolytic urokinase (p = 0.0034). Conclusion: We found considerable variability and lack of evidence for a net improvement in outcome after intra-arterial therapy relative to predicted natural history, substantiating the need for a prospective comparison with best medical therapy. The features associated with better performers identified here may be useful in designing such a trial.

Zinc-containing neuronal innervation of the septal nuclei

A zinc-specific retrograde transport method has been employed to map the zinc-containing neuronal projections to the septal nuclei. Sodium selenite was infused iontophoretically into the lateral or medial septal nuclei to precipitate vesicular zinc as ZnSe in situ, and the neurons that were subsequently labeled by the retrograde transport of ZnSe to their perikarya were mapped. Zinc-containing cells of origin were found only in the hippocampal formation and predominantly in two regions thereof: (i) in s. oriens and deep s. pyramidale of fields CA3a and CA2 and (ii) in s. pyramidale of distal CA1 and adjacent prosubiculum.

Glycoprotein IIb/IIIa antagonists in acute ischaemic stroke: current status and future directions.

Glycoprotein (GP) IIb/IIIa receptors on the surface of platelets play a critical role in thrombosis. Intravenous GP IIb/IIIa antagonists abciximab, tirofiban and eptifibatide have demonstrated efficacy in acute coronary syndromes when combined with heparin, aspirin, clopidogrel and percutanous coronary interventions. Results have been less consistent in acute ischaemic stroke. Preclinical data support the potential benefit of these agents both in the microcirculation and in aiding clot lysis. While phase I and II trials of abciximab as the sole agent employing dosages comparable with those used in coronary syndromes were promising, the pivotal phase III trial was abandoned because of an unfavourable benefit-to-risk ratio. New preliminary platelet inhibition measurements from our group suggest that cardiac dosages were likely to be too high for stroke patients. Exploration of lower dosages of abciximab and potentiation with time-limited weight-based heparin along with platelet aggregation inhibition measurement is continuing on a smaller scale. At present, the most common usage of GP IIb/IIIa antagonists in stroke are as adjunctive agents to thrombolysis by intravenous and intra-arterial routes. Substantial progress is likely to require a better understanding of the mechanism of actions and unique pharmacology of GP IIb/IIIa antagonists in ischaemic stroke.

Natural and Nosocomial Infection in a Patient with West Nile Encephalitis and Extrapyramidal Movement Disorders

Since its first recognition in North America in 1999, West Nile virus (WNV) has spread rapidly across the continent, but in many communities, rapid diagnostic tests for detection of WNV infection are not fully available. We describe a patient with extrapyramidal movement disorders and changes in the basal ganglia noted on magnetic resonance images that are characteristic of other flavivirus encephalitides and may help in the recognition of patients with West Nile encephalitis. Detailed molecular analysis suggested that, although our patient received a blood transfusion infected with WNV, the virus that caused his initial infection and encephalitis was probably acquired naturally from a mosquito.

Restarting Anticoagulant Therapy After Intracranial Hemorrhage: A Systematic Review and Meta-Analysis

Background and Purpose— The safety and efficacy of restarting anticoagulation therapy after intracranial hemorrhage (ICH) remain unclear. We performed a systematic review and meta-analysis to summarize the associations of anticoagulation resumption with the subsequent risk of ICH recurrence and thromboembolism. Methods— We searched published medical literature to identify cohort studies involving adults with anticoagulation-associated ICH. Our predictor variable was resumption of anticoagulation. Outcome measures were thromboembolic events (stroke and myocardial infarction) and recurrence of ICH. After assessing study heterogeneity and publication bias, we performed a meta-analysis using random-effects models to assess the strength of association between anticoagulation resumption and our outcomes. Results— Eight studies were eligible for inclusion in the meta-analysis, with 5306 ICH patients. Almost all studies evaluated anticoagulation with vitamin K antagonists. Reinitiation of anticoagulation was associated with a significantly lower risk of thromboembolic complications (pooled relative risk, 0.34; 95% confidence interval, 0.25–0.45; Q=5.12, P for heterogeneity=0.28). There was no evidence of increased risk of recurrent ICH after reinstatement of anticoagulation therapy, although there was significant heterogeneity among included studies (pooled relative risk, 1.01; 95% confidence interval, 0.58–1.77; Q=24.68, P for heterogeneity <0.001). No significant publication bias was detected in our analyses. Conclusions— In observational studies, reinstitution of anticoagulation after ICH was associated with a lower risk of thromboembolic complications and a similar risk of ICH recurrence. Randomized clinical trials are needed to determine the true risk–benefit profile of anticoagulation resumption after ICH.

A Method to Determine Stroke Trial Success Using Multidimensional Pooled Control Functions

BACKGROUND AND PURPOSE Many early phase trials in stroke have not been subsequently confirmed. Randomization balance in baseline factors that influence outcome are difficult to achieve and may be partly responsible for misleading early results. We hypothesized that comparison with an outcome function derived from a large number of pooled control arms would mitigate these randomization problems and provide a reliable predictor for decision-making before proceeding to later phase trials. We developed such a model and added a novel feature of generation of multidimensional 95% prediction surfaces by which individual studies could be compared. We performed a proof-of-principle study with published clinical trials, determining whether our method correctly identified known outcomes. METHODS The control arms from all randomized, controlled trials for acute stroke with >or=10 subjects, including baseline National Institute of Health Stroke Scale, age, and 3-month outcomes published between 1994 and May 2008, were identified. A Matlab program (PPREDICTS) was written to generate outcome functions based on these parameters. Published treatment trials were compared with these 95% intervals to determine whether it successfully identified positive and negative trials. RESULTS Models of mortality and functional outcome were successfully generated (mortality: R(2)=0.69; functional outcome, modified Rankin Scale 0 to 2: R(2)=0.81; both P<0.0001). The National Institute of Neurological Diseases and Stroke intravenous recombinant tissue plasminogen activator trial and 3 studies yet to be subjected to Phase III study had modified Rankin Scale 0 to 2 outcomes above the 95% prediction interval. Sixteen treatment arm outcomes fell within prediction surface bounds. This group included 2 major trials, Stroke-Acute Ischemic NXY Treatment and Abciximab Emergent Stroke Treatment Trial, that initially appeared promising but went on to negative Phase III results. CONCLUSIONS This proof-of-principle analysis confirmed all positive and negative clinical stroke trial results and identified some promising therapies. The use of a pooled standard treatment group function combined with statistical bounds may improve selection of early studies for further study. This method may be applicable to any condition in which baseline factors influence outcome and at any stage of the development process.

Initial Safety Experience of Abciximab and Heparin for Acute Ischemic Stroke

Methods We offered abciximab on an informed consent basis to 14 patients with ischemic stroke ineligible for intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) [4] . Eligibility for treatment was extended to patients with time of onset to 6 h for anterior circulation and 24 h for basilar artery thrombosis, patients with recent myocardial infarction, cardiac surgery or intracardiac procedures, and patients with therapeutic extensions of coagulation parameters if partial thromboplastin time was less than 90 and international normalized ratio less than 2.5. The deviations from i.v. rt-PA guidelines were institutional adaptations for this treatment regimen. Periodic review, after each 5 subjects, of the accumulating data was performed to assess for unacceptable hemorrhagic complications ( 1 25% hemorrhagic transformation rate or hemorrhage requiring intervention). An initial i.v. bolus of 0.20 mg/kg of abciximab was given over 1 min. Subsequently, the treatment team decided on whether to administer an i.v. infusion of abciximab over 12 h at a dose of Introduction Studies on options to treat acute stroke patients who are already receiving anticoagulants are limited. By contrast, there is extensive experience with combining heparin and abciximab (ReoPro TM , Centecor), a glycoprotein IIb/IIIa inhibitor, in the setting of coronary interventions [1] . Abciximab has emerged as a promising alternative in ischemic stroke as well, but concomitant use of anticoagulants has been prohibited in randomized trials [2, 3] . Given its

A Matching Algorithm to Address Imbalances in Study Populations Application to the National Institute of Neurological Diseases and Stroke Recombinant Tissue Plasminogen Activator Acute Stroke Trial

Background and Purpose— Outcome from stroke is highly dependent on baseline conditions. Patients with stroke have a wide range of severities, ages, and etiologies and it has proven difficult to achieve randomization of key variables in clinical trials. We present a new post hoc approach to achieve balance among selected variables. To illustrate the approach, we rebalanced the National Institute of Neurological Diseases and Stroke Recombinant Tissue Plasminogen Activator trial, in which the contribution of baseline imbalances continues to be debated. Methods— We selected baseline stroke severity (National Institutes of Health Stroke Scale), age, and glucose as matching criteria. The closest matched placebo and treated subjects were identified based on nearness to each other in 3-dimensional Euclidean space. Matching was performed within the quintiles of National Institutes of Health Stroke Scale that have been previously used to assess balance. Subjects who could not be matched were eliminated. Outcomes were assessed using the original specified National Institute of Neurological Diseases and Stroke trial measures. Results— We successfully matched the 2 arms resulting in nearly identical baseline characteristics and distribution among quintiles. Despite fewer subjects after outlier elimination, the primary outcome measures remained significantly improved. After rebalancing, the magnitude of benefit was reduced by 13% to 23%. Benefit was apparent mostly in the large vessel occlusion subtype. Conclusion— This study demonstrated the feasibility of rebalancing individual subjects within a randomized trial. After rebalancing and outlier elimination, recombinant tissue plasminogen activator continued to demonstrate improved outcome. That the apparent treatment effect was reduced suggests that imbalances contributed to the magnitude of the original National Institute of Neurological Diseases and Stroke outcomes. This method could in theory be applied to any data set to find matched subjects for outcome or other analyses.