T.-H. Cho

The role of the cerebral capillaries in acute ischemic stroke: the extended penumbra model

The pathophysiology of cerebral ischemia is traditionally understood in relation to reductions in cerebral blood flow (CBF). However, a recent reanalysis of the flow-diffusion equation shows that increased capillary transit time heterogeneity (CTTH) can reduce the oxygen extraction efficacy in brain tissue for a given CBF. Changes in capillary morphology are typical of conditions predisposing to stroke and of experimental ischemia. Changes in capillary flow patterns have been observed by direct microscopy in animal models of ischemia and by indirect methods in humans stroke, but their metabolic significance remain unclear. We modeled the effects of progressive increases in CTTH on the way in which brain tissue can secure sufficient oxygen to meet its metabolic needs. Our analysis predicts that as CTTH increases, CBF responses to functional activation and to vasodilators must be suppressed to maintain sufficient tissue oxygenation. Reductions in CBF, increases in CTTH, and combinations thereof can seemingly trigger a critical lack of oxygen in brain tissue, and the restoration of capillary perfusion patterns therefore appears to be crucial for the restoration of the tissue oxygenation after ischemic episodes. In this review, we discuss the possible implications of these findings for the prevention, diagnosis, and treatment of acute stroke.

Ischemic stroke:etiologic work-up with multidetector CT of heart and extra-and intracranial arteries

PURPOSEnTo assess the potential of a single-session multidetector computed tomography (CT) protocol, as compared with established methods, for the etiologic work-up of acute ischemic stroke.nnnMATERIALS AND METHODSnPatients found to have recently experienced an ischemic stroke were recruited for this prospective study after institutional review board approval was obtained. Each patient was scheduled for two evaluation strategies: (a) a standard approach involving transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE), duplex ultrasonography (US) of the neck vessels, and magnetic resonance (MR) angiography of the neck and brain vessels; and (b) a protocol involving single-session multidetector CT of the heart, neck, and brain vessels. The authors sought to determine the major etiologic factors of stroke, including cardiac sources of embolism and atheroma of the aortic arch and the extra- and intracranial vessels, by using both strategies.nnnRESULTSnMultidetector CT, MR imaging, and duplex US were performed in 46 patients, 39 of whom also underwent TEE. The sensitivity and specificity of multidetector CT were 72% (18 of 25 cases) and 95% (20 of 21 cases), respectively, for detection of cardiac sources and 100% (24 of 24 cases) and 91% (20 of 22 cases), respectively, for detection of major arterial atheroma. For the 46 cases of stroke, the final etiologic classifications determined by using the standard combination approach were cardiac sources in 20 (44%) cases, major arterial atheroma in nine (20%), multiple sources in four (9%), and cryptogenic sources in 13 (28%). Multidetector CT facilitated correct etiologic classification for 38 (83%) of the 46 patients.nnnCONCLUSIONnMultidetector CT is a promising tool for etiologic assessment of ischemic stroke, although the identification of minor cardiac sources with this examination requires the establishment of robust criteria.

Cyclosporine in acute ischemic stroke

Objectives: We examined whether IV administration of cyclosporine in combination with thrombolysis might reduce cerebral infarct size. Methods: Patients aged 18 to 85 years, presenting with an anterior-circulation stroke and eligible for thrombolytic therapy, were enrolled in this multicenter, single-blinded, controlled trial. Fifteen minutes after randomization, patients received either an IV bolus injection of 2.0 mg/kg cyclosporine (Sandimmune, Novartis) or placebo. The primary endpoint was infarct volume on MRI at 30 days. Secondary endpoints included infarct volume according to the site (proximal/distal) of arterial occlusion and recanalization after thrombolysis. Results: From October 2009 to July 2013, 127 patients were enrolled. The primary endpoint was assessed in 110 of 127 patients. The reduction of infarct volume in the cyclosporine compared with the control group was overall not significant (21.8 mL [interquartile range, IQR 5.1, 69.2 mL] vs 28.8 mL [IQR 7.7, 95.0 mL], respectively; p = 0.18). However, in patients with proximal occlusion and effective recanalization, infarct volume was significantly reduced in the cyclosporine compared with the control group (14.9 mL [IQR 1.3, 23.2 mL] vs 48.3 mL [IQR 34.5, 118.2 mL], respectively; p = 0.009). Conclusions: Cyclosporine was generally not effective in reducing infarct size. However, a smaller infarct size was observed in patients with proximal cerebral artery occlusion and efficient recanalization. Classification of evidence: This study provides Class I evidence that in patients with an acute anterior-circulation stroke, thrombolysis plus IV cyclosporine does not significantly decrease 30-day MRI infarct volume compared with thrombolysis alone.

Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke A Retrospective Pooled Analysis

Background and Purpose— The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large data set from preclinical studies, to examine the effects of early versus late administration of intravenous recombinant tissue-type plasminogen activator. Methods— We collected data from 26 individual studies from 9 international centers (13 researchers; 716 animals) that compared recombinant tissue-type plasminogen activator with controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3 hours) versus late (≥3 hours) drug administration. Final infarct volumes, assessed by histology or magnetic resonance imaging, were compared in each study, and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. Results— When compared with saline controls, early recombinant tissue-type plasminogen activator administration was associated with a significant benefit (absolute difference, −6.63 mm3; 95% confidence interval, −9.08 to −4.17; I2=76%), whereas late recombinant tissue-type plasminogen activator treatment showed a deleterious effect (+5.06 mm3; 95% confidence interval, +2.78 to +7.34; I2=42%; Pint<0.00001). Results remained unchanged after subgroup analyses. Conclusions— Our results provide the basis needed for the design of future preclinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multicenter trial would require 123 animals per group instead of 40 for a single-center trial.

Safety of early initiation of rivaroxaban or dabigatran after thrombolysis in acute ischemic stroke.

The introduction of direct oral anticoagulants (DOA) in the early stage of cerebral infarction after thrombolysis may reduce the recurrence rate but raises safety concern. We sought to study the feasibility and safety of the introduction of rivaroxaban or dabigatran in this context. Thirty-four consecutive patients admitted for ischemic stroke related to non-valvular atrial fibrillation in whom DOA were given within the first two weeks following intravenous rt-PA were studied. A clinical and radiological monitoring protocol was established to ensure the safety of the prescription. None of the patients experienced symptomatic hemorrhagic transformation or a symptomatic recurrent ischemic event after early rivaroxaban or dabigatran introduction.

Acute Headache Followed by Focal Neuropsychological Impairment in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Occasionally, patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) present atypical features such as confusion, coma, or nonconvulsive status epilepticus. Acute focal neuropsychological syndrome revealing the disease has been poorly documented. We report the atypical presentation of two patients in whom CADASIL was revealed by an episode of headache followed by focal neuropsychological impairment.

Multilevel Assessment of Atherosclerotic Extent Using a 40-Section Multidetector Scanner after Transient Ischemic Attack or Ischemic Stroke

BACKGROUND AND PURPOSE: The first part of this study assessed the potential of MDCT with a CTA examination of the aorta and the coronary, cervical, and intracranial vessels in the etiologic work-up of TIA or ischemic stroke compared with established imaging methods. The objective of the second part of this study was to assess the atherosclerotic extent by use of MDCT in these patients. MATERIALS AND METHODS: From August 2007 to August 2011, a total of 96 patients with ischemic stroke or TIA without an evident cardioembolic source were enrolled. All patients underwent MDCT. Atherosclerotic extent was classified in 0, 1, 2, 3, and 4 atherosclerotic levels according to the number of arterial territories (aortic arch, coronary, cervical, intracranial) affected by atherosclerosis defined as ≥50% cervical, intracranial, or coronary stenosis or ≥4-mm aortic arch plaque. RESULTS: There were 91 patients who had an interpretable MDCT. Mean age was 67.4 years (± 11 years), and 75 patients (83.3%) were men. The prevalence of 0, 1, 2, 3, and 4 atherosclerotic levels was 48.3%, 35.2%, 12.1%, 4.4%, and 0%, respectively. Aortic arch atheroma was found in 47.6% of patients with 1 atherosclerotic level. The combination of aortic arch atheroma and cervical stenosis was found in 63.6% of patients with ≥2 atherosclerotic levels. Patients with ≥2 atherosclerotic levels were older than patients with < 2 atherosclerotic levels (P = .04) in univariate analysis. CONCLUSIONS: MDCT might be useful to assess the extent of atherosclerosis. It could help to screen for high-risk patients who could benefit from a more aggressive preventive strategy.