Ramy El Khoury

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.

Progenitor Cell Therapy for the Treatment of Central Nervous System Injury: A Review of the State of Current Clinical Trials

Recent preclinical work investigating the role of progenitor cell therapies for central nervous system (CNS) injuries has shown potential neuroprotection in the setting of traumatic brain injury (TBI), spinal cord injury (SCI), and ischemic stroke. Mechanisms currently under investigation include engraftment and transdifferentiation, modulation of the locoregional inflammatory milieu, and modulation of the systemic immunologic/inflammatory response. While the exact mechanism of action remains controversial, the growing amount of preclinical data demonstrating the potential benefit associated with progenitor cell therapy for neurological injury warrants the development of well-controlled clinical trials to investigate therapeutic safety and efficacy. In this paper, we review the currently active or recently completed clinical trials investigating the safety and potential efficacy of bone marrow-derived progenitor cell therapies for the treatment of TBI, SCI, and ischemic stroke. Our review of the literature shows that while the preliminary clinical trials reviewed in this paper offer novel data supporting the potential efficacy of stem/progenitor cell therapies for CNS injury, a great deal of additional work is needed to ensure the safety, efficacy, and mechanisms of progenitor cell therapy prior to widespread clinical trials.

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.

Von Willebrand Factor Drives the Association Between Elevated Factor VIII and Poor Outcomes in Patients With Ischemic Stroke

Background and Purpose— Despite clear roles of factor VIII (FVIII) and von Willebrand factor (vWF) in thrombosis, few studies have examined the relationship of these factors with acute ischemic stroke (AIS). We sought to determine whether concurrent elevation in FVIII and vWF was associated with adverse events and outcomes. Methods— From our prospective stroke registry, patients consecutively admitted with AIS between July 2008 and October 2013 were included if both FVIII and vWF were measured during admission. The primary outcome was the modified Rankin Scale score on discharge. Results— Among 1453 cases in our stroke registry, 148 patients with AIS met inclusion criteria; 62 patients (41.9%) had FVIII−/vWF−, 16 patients (10.8%) had FVIII+/vWF−, and 51 patients (34.5%) had FVIII+/vWF+. In the fully adjusted model, patients with FVIII+/vWF+ had increased odds of inpatient complications (odds ratio, 8.6; 95% confidence interval, 1.58–46.85; P=0.013) and neuroworsening (odds ratio, 3.2; 95% confidence interval, 1.18–8.73; P=0.022) than patients with FVIII−/vWF−. Adjusted for age, baseline stroke severity, and glucose, patients with FVIII+/vWF+ had increased odds of poor functional outcome (modified Rankin Scale>2; odds ratio, 2.87; 95% confidence interval, 1.16–7.06; P=0.021) than patients with FVIII−/vWF−. Conclusions— Concurrent FVIII/vWF elevation predicts higher odds of inpatient complications, neuroworsening, and worse functional outcomes for patients with AIS compared with patients with normal levels. Our findings suggest that FVIII and vWF levels may serve as clinically useful stroke biomarkers by providing risk profiles for patients with AIS.

Intracranial Atherosclerosis Is Associated with Progression of Neurological Deficit in Subcortical Stroke

Background: Progression of neurological deficit (PND) is a frequent complication of acute subcortical ischemic stroke (SCS). The role of intracranial atherosclerosis (IAS) in PND is controversial. Our goal was to evaluate IAS on admission, as predictor of PND in SCS patients. Methods: SCS patients were identified from our prospective database from 2004 to 2008. Clinical and laboratory data were collected from charts, and radiographic data from original radiographs. The proximal intracranial arteries were graded as patent, irregular, stenotic, or occlusion. IAS was defined as irregularity or stenosis. PND was defined as a change in the National Institutes of Health Stroke Scale >1 point. Results: Two hundred and two SCS patients were identified. In 14%, PND occurred at a median of 2 days from onset. Univariate analysis by infarct location showed the following to be associated with PND: for anterior circulation infarcts (centrum semiovale/basal ganglia), M1 atherosclerosis (p = 0.042); for posterior circulation infarcts, vertebral artery atherosclerosis (p = 0.018). For both groups, we found a non-significant association with age (p = 0.2) and HbA1c levels (p = 0.095). No association was found with admission glucose levels. Multivariate analysis showed the following association with PND: for anterior circulation infarcts, M1 atherosclerosis (OR 4.7; 95% CI 1.2–18.8; p = 0.03); for pontine infarcts, vertebral artery atherosclerosis (OR 5.8; 95% CI 1.1–29.4; p = 0.033). There was an increase in PND likelihood with an increasing number of atherosclerotic vessels. Discussion: In our cohort of SCS patients, PND was associated with IAS of the responsible vessels. These results suggest a role for IAS in the pathogenesis of PNF in SCS patients.

Current practice versus willingness to enroll in clinical trials: Paradox among vascular neurologists about treatment for acute ischemic stroke

Background and Purpose— Clinical trials are assessing the efficacy of fibrinolysis in extended time windows for acute ischemic stroke. Methods— An Internet-based survey was sent to 400 US vascular neurologists affiliated with a university to assess whether there are consensus opinions on how they treat patients beyond 3 hours from symptom onset and which patients they are willing to enroll into clinical trials of fibrinolysis for acute ischemic stroke. Results— We received 161 responses; 81% were male. Ninety-three percent of respondents treat patients with intravenous tissue plasminogen activator beyond 3 hours. More than 80% were treated beyond 3 hours with intra-arterial therapy (IAT). When asked if IAT improves stroke outcome, >50% selected the choice of “yes for middle cerebral artery and basilar occlusions” and only 2% selected the choice that “IAT does not improve outcome.” Over half believe that imaging could be used to approximate the penumbra but with improvements to better identify salvageable tissue. Eighty-seven percent were willing to enroll patients into a placebo-controlled intravenous thrombolysis beyond 3 hours. For IAT trials, >80% would randomize beyond 3 hours with or without prior intravenous treatment. Conclusions— Vascular neurologists have been treating acute ischemic stroke beyond 3 hours with intravenous tissue plasminogen activator even before the American Heart Association guidelines supported extending the therapeutic window. There is a paradox among the respondents willing to enroll patients into trials involving IAT given that a majority is offering IAT as part of their practice. These results suggest that clinical practice may impair enrollment into trials testing reperfusion therapies for acute ischemic stroke.

Resolution of Internal Carotid Dissection with Middle Cerebral Artery Occlusion in Pregnancy

Introduction. Cervical artery dissection (CAD) is a common cause of stroke in younger patients. While the incidence of stroke in pregnancy is increasing, CAD remains a rare cause of ischemic stroke in the pregnant population, with only 30 cases described in the literature, most in the postpartum period. Methods. The case of a pregnant patient at 18 weeks of gestation presenting with CAD and ischemic stroke following intercourse is discussed. Discussion. CAD results from an intimal tear in the carotid artery, allowing accumulation of blood in the vessel wall. Stroke results from embolization of thrombogenic material in the wall. Etiology includes minor trauma, connective tissue disorders, or anatomic variations of the carotid artery. Most patients present with headache and/or neck pain, while ischemic symptoms are seen in at least 50% of patients. In the pregnant population, imaging with MRI or MRA of the head and neck aids in diagnosis. Once the diagnosis is made, patients are treated with either anticoagulation or antiplatelet medications. The optimal treatment in both pregnant and nonpregnant patients has not been well-studied. Conclusion. CAD is an important diagnosis to consider in a pregnant patient with persistent headache, especially if neurological symptoms are present. Imaging should be quickly obtained so treatment can be initiated.

MSCs for the Treatment of Stroke, Spinal Cord Injury, and Traumatic Brain Injury: From Bench Work to Clinical Trials

Stroke, spinal cord injury, and traumatic brain injury are the major three causes of central nervous system injury. After the acute phase, most patients are left with significant motor, cognitive, and social impairments. Few treatments exist and there are no current therapeutic interventions altering their underlying pathological processes via tissue salvage, support, repair, or replacement at the cellular or subcellular level. Recent evidence suggests that the cell-based therapy exerts therapeutic benefits in relevant preclinical animal models. Furthermore, some cell types, like MSCs, have advanced into clinical trials. Here, we present the current status of MSCs in stroke, SCI, and TBI therapy from preclinical studies to clinical trials, with an emphasis on dosage, timing, and routes of delivery. We also discuss possible cellular and molecular mechanisms of action that mediate the effects of MSCs in these different disease models. Finally, we end with a discussion of important issues that require future study.

Factor VIII in Acute Cerebral Ischemia Pilot Study: Biomarker in Patients With Large Vessel Occlusion?:

We conducted a prospective serial laboratory cohort study to assess the correlation of factor VIII (FVIII) levels in response to thrombolysis in patients with large vessel occlusion (LVO) and acute ischemic stroke (AIS). Patients with AIS with anterior circulation LVO were eligible for enrollment if treated within 4.5 hours from last seen normal with intravenous tissue plasminogen activator (tPA). Patients (n = 29) had a mean age of 71 years and median National Institute of Health Stroke Scale of 14. Baseline pre-tPA FVIII was not significantly correlated with clot burden score (−0.147, P = .447) or vessel recanalization (−0.133, P = .499). Median FVIII decreased significantly from baseline to 6 hours post-tPA (282% to 161%, P = .002), but delta in FVIII level did not correlate with vessel recanalization (0.013, P = .948). There was no difference between median FVIII level at baseline and 90 days post-AIS. FVIII level decreased significantly after tPA, but baseline FVIII level and early change in FVIII level were not significant predictors of clot burden, vessel recanalization after thrombolysis, or symptomatic hemorrhage.