Vivek Misra

Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia

Background: Patients with acute neurologic symptoms may have other causes simulating ischemic stroke, called stroke mimics (SM), but they may also have averted strokes that do not appear as infarcts on neuroimaging, which we call neuroimaging-negative cerebral ischemia (NNCI). We determined the safety and outcome of IV thrombolysis within 3 hours of symptom onset in patients with SM and NNCI. Methods: Patients treated with IV tissue plasminogen activator (tPA) within 3 hours of symptom onset were identified from our stroke registry from June 2004 to October 2008. We collected admission NIH Stroke Scale (NIHSS) score, modified Rankin score (mRS), length of stay (LOS), symptomatic intracerebral hemorrhage (sICH), and discharge diagnosis. Results: Among 512 treated patients, 21% were found not to have an infarct on follow-up imaging. In the SM group (14%), average age was 55 years, median admission NIHSS was 7, median discharge NIHSS was 0, median LOS was 3 days, and there were no instances of sICH. The most common etiologies were seizure, complicated migraine, and conversion disorder. In the NNCI group (7%), average age was 61 years, median admission NIHSS was 7, median discharge NIHSS was 0, median LOS was 3 days, and there were no instances of sICH. Nearly all SM (87%) and NNCI (91%) patients were functionally independent on discharge (mRS 0–1). Conclusions: Our data support the safety of administering IV tissue plasminogen activator to patients with suspected acute cerebral ischemia within 3 hours of symptom onset, even when the diagnosis ultimately is found not to be stroke or imaging does not show an infarct.

Intravenous autologous bone marrow mononuclear cells for ischemic stroke

Cellular therapy is an investigational approach for stroke. Mononuclear cells (MNCs) from the bone marrow reduce neurological deficits in animal stroke models. We determined if autologous MNC infusion was feasible and safe in patients with ischemic stroke.

Stem Cells as an Emerging Paradigm in Stroke 3 Enhancing the Development of Clinical Trials

Cell-based therapy continues to grow as a new field to explore investigational treatments for stroke. Leaders from academia and industry convened an inaugural meeting in 2007 with members of the National Institutes of Health and Food and Drug Administration (FDA) to generate consensus-based guidelines on the development of cell therapies for stroke, entitled “Stem Cells as an Emerging Paradigm in Stroke” (STEPS).1 These guidelines focused on preclinical studies that are considered important as part of a development program to support clinical testing of cell therapies. The STEPS meeting also provided recommendations on the conduct of early-stage clinical trials. Given the rapid advances in the field, a second meeting was held in 2009 to update and expand these guidelines, which were published as STEPS 2.2 In December 2011, investigators in academia, industry leaders, and members of the National Institutes of Health and FDA gathered at a third meeting, STEPS 3, to discuss emerging data on the mechanisms of action of cell therapy, the barriers to successful translation from animal models to patients, and the design of current clinical trials for acute and chronic stroke. Since the prior STEPS meeting, there are now several active cell therapy platforms for stroke and other neurological disorders, in stages that range from preclinical to clinical trials, and with sponsors that include industry, the National Institutes of Health, and the California Institute of Regenerative Medicine. As the field continues to progress and as pilot clinical studies are starting to show safety for some cell types, it has become necessary to formulate a new set of guidelines that address topics not covered in prior STEPS publications. Specifically, the current document reflects a compilation of recommendations that focus on more advanced stages of clinical testing, as well as the testing of cell therapies in a broader …

Intracerebral Hemorrhage in Cocaine Users

Background and Purpose— Cocaine is a cause of intracerebral hemorrhage (ICH), but there are no large studies that have characterized the location, pathology, and outcome of patients with cocaine-associated ICH. Methods— We performed a retrospective analysis of all patients admitted to our stroke service from 2004 to 2007 who had nontraumatic ICH and urine drug screens positive for cocaine and compared them with similar patients who had negative drug screens for cocaine. Results— We identified 45 patients with cocaine-associated ICH and 105 patients with cocaine-negative ICH. There were no significant differences in age or gender, but there was a significantly higher incidence of black patients in the cocaine-positive group. Cocaine-associated ICH patients had higher admission blood pressures, significantly more subcortical hemorrhages, and higher rates of intraventricular hemorrhage compared to patients with cocaine-negative ICH. Cocaine-positive patients had worse functional outcome, defined as modified Rankin Scale score >3 at the time of discharge (OR, 4.90; 95% CI, 2.19–10.97), and were less likely to be discharged home or to inpatient rehabilitation. Patients with cocaine-associated ICH were nearly 3-times more likely to die during their acute hospitalization when compared to cocaine-negative patients. Conclusion— Recent cocaine ingestion is associated with hemorrhages that occur more frequently in subcortical locations, have a higher risk of intraventricular hemorrhage, and have a poor prognosis compared to patients with cocaine-negative, spontaneous ICH.

Stem cell therapy in ischemic stroke Role of IV and intra-arterial therapy

Objective: Cell-based therapies are being investigated as an adjunct to IV thrombolysis or mechanical thrombectomy in ischemic stroke. This review summarizes the potential applications as well as challenges of intravascular cell delivery in ischemic stroke. Method: We conducted a search of Medline as well as the clinicaltrials.gov Web site for all ongoing human clinical studies using stem cells in ischemic stroke patients. Result: The pros and cons of the various donor cell types and routes of cell delivery, including intravascular delivery, in ischemic stroke are discussed. In addition, the potential challenges in translation from bench to bedside, the optimal techniques for intravascular cell delivery, and an updated comprehensive list of ongoing clinical trials in ischemic stroke are highlighted. Conclusions: Stem cells have shown a promising role in ischemic stroke, in preclinical studies as well as initial pilot studies. Further studies are needed to assess intravascular cell therapy as a potential adjunct to thrombolysis or mechanical thrombectomy in ischemic stroke.

Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC).

Rationale Preclinical work demonstrates that the transcription factor peroxisome proliferator-activated receptor gamma plays an important role in augmenting phagocytosis while modulating oxidative stress and inflammation. We propose that targeted stimulation of phagocytosis to promote efficient removal of the hematoma without harming surrounding brain cells may be a therapeutic option for intracerebral hemorrhage. Aims The primary objective is to assess the safety of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in increasing doses for three-days followed by a maintenance dose, when administered to patients with spontaneous intracerebral hemorrhage within 24 h of symptom onset compared with standard care. We will determine the maximum tolerated dose of pioglitazone. Study Design This is a prospective, randomized, blinded, placebo-controlled, dose-escalation safety trial in which patients with spontaneous intracerebral hemorrhage are randomly allocated to placebo or treatment. The Continual Reassessment Method for dose finding is used to determine the maximum tolerated dose of pioglitazone. Hematoma and edema resolution is evaluated with serial magnetic resonance imaging (MRI) at specified time points. Functional outcome will be evaluated at three- and six-months. Outcomes The primary safety outcome is mortality at discharge. Secondary safety outcomes include mortality at three-months and six-months, symptomatic cerebral edema, clinically significant congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Radiographic outcomes will explore the time frame for resolution of 25%, 50%, and 75% of the hematoma. Clinical outcomes are measured by the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, modified Rankin Scale, Stroke Impact Scale-16, and EuroQol at three- and six-months.

Acute Ischemic Stroke Treated with Intravenous Tissue Plasminogen Activator in a Patient Taking Dabigatran with Radiographic Evidence of Recanalization

Dabigatran etexelate is a new oral direct thrombin inhibitor that has been approved by the US Food and Drug Administration to prevent stroke in patients with nonvalvular atrial fibrillation. A 51-year-old man with a history of atrial fibrillation who was taking dabigatran presented with an acute ischemic stroke. The patient had a normal international normalized ratio, activated partial thromboplastin time, and an elevated thrombin time of 26.4 seconds. Recanalization of the middle cerebral artery with intravenous tissue plasminogen activator was apparent on digital subtraction angiography, and there was no evidence of intracerebral hemorrhage on the repeat computed tomographic scan. This is the first report of a patient who was taking dabigatran etexilate and who had an ischemic stroke caused by a middle cerebral artery occlusion, with an elevated thrombin time and radiographic recanalization with intravenous tissue plasminogen activator without evidence of hemorrhagic transformation.

Intravenous Tissue Plasminogen Activator in Patients With Cocaine-Associated Acute Ischemic Stroke

Background and Purpose— The safety of thrombolytic therapy in patients with cocaine-associated acute ischemic stroke (CIS) is unknown. Methods— We conducted a retrospective review of patients with CIS who presented to our stroke center. Thrombolytic treatment was compared between cocaine-positive (n=29) and cocaine-negative (n=75) patients. We also compared patients with CIS treated with tissue plasminogen activator versus those who did not receive tissue plasminogen activator (n=58). Safety outcomes were determined by the incidence of symptomatic intracerebral hemorrhage, in-hospital mortality, and modified Rankin Scale at hospital discharge. Results— There were no complications in tissue plasminogen activator-treated patients with CIS. Cocaine-positive and cocaine-negative treated patients had similar stroke severity and safety outcomes. Patients with CIS treated with tissue plasminogen activator had more severe strokes on baseline National Institutes of Health Stroke Scale but similar safety outcomes compared with nontreated patients with CIS. Conclusion— Thrombolytic therapy for CIS appears to be safe in this small study. Further research is needed to more definitively assess safety and efficacy of tissue plasminogen activator for CIS.

Pharmacological Deep Vein Thrombosis Prophylaxis Does Not Lead to Hematoma Expansion in Intracerebral Hemorrhage With Intraventricular Extension

Background and Purpose— Patients with intracerebral hemorrhage (ICH) are at high risk for development of deep venous thrombosis. Current guidelines state that low-dose subcutaneous low molecular weight heparin or unfractionated heparin may be considered at 3 to 4 days from onset. However, insufficient data exist on hematoma volume in patients with ICH before and after pharmacological deep venous thrombosis prophylaxis, leaving physicians with uncertainty regarding the safety of this practice. Methods— We identified patients from our stroke registry (June 2003 to December 2007) who presented with ICH only or ICH+intraventricular hemorrhage and received either low molecular weight heparin subcutaneously or unfractionated heparin within 7 days of admission and had a repeat CT scan performed within 4 days of starting deep venous thrombosis prophylaxis. We calculated the change in hematoma volume from the admission and posttreatment CTs. Hematoma volume was calculated using the ABC/2 method and intraventricular hemorrhage volumes were calculated using a published method of hand drawn regions of interest. Results— We identified 73 patients with a mean age of 63 years and median National Institutes of Health Stroke Scale score 11.5. The mean baseline total hematoma volume was 25.8 mL±23.2 mL. There was an absolute change in hematoma volume from pre- and posttreatment CT of −4.3 mL±11.0 mL. Two patients developed hematoma growth. Repeat analysis of patients given pharmacological deep venous thrombosis prophylaxis within 2 or 4 days after ICH found no increase in hematoma size. Conclusions— Pharmacological deep venous thrombosis prophylaxis given subcutaneously in patients with ICH and/or intraventricular hemorrhage in the subacute period is generally not associated with hematoma growth.

Intra-Arterial Delivery of Cell Therapies for Stroke

Cell therapy is a novel investigational approach to enhance stroke recovery. Intra-arterial (IA) delivery has the potential advantage of selectively targeting cell therapies to the ischemic brain tissue. Over the past 10 years, IA cell delivery has been under investigation in patients with cardiac and peripheral vascular disease, and these studies have reported promising results. This article reviews the trial methodology and procedural details of these studies and discusses the rationale and challenges in designing IA cell therapy trials for ischemic stroke.