Salvageable Brain Tissue Research Articles

Advances in intravenous thrombolytic therapy for treatment of acute stroke.

Intravenous tissue plasminogen activator (tPA) is an effective therapy for treatment of acute ischemic stroke when administered within 3 hours of symptom onset. Three large randomized clinical trials that have attempted to extend the time window for tPA treatment beyond 3 hours have failed to demonstrate convincing evidence of efficacy. A recently published prospective, monitored, multicenter study of 389 patients, who were treated with tPA for ischemic stroke at 57 medical centers (24 academic, 33 community) across the United States, demonstrated favorable outcomes and low rates of symptomatic intracerebral hemorrhage. Recent advances in neuroimaging, including diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI), have the potential to differentiate salvageable ischemic brain tissue from irreversibly injured tissue. Preliminary data suggest that acute stroke patients who present with a PWI lesion that is considerably larger than the initial DWI lesion may be good candidates for intravenous thrombolysis, even beyond 3 hours after symptom onset. Additional research is required to clarify the optimal use of these diagnostic techniques and their cost-effectiveness.

Late temporal lobe necrosis in patients with nasopharyngeal carcinoma: evaluation with combined multi-section diffusion weighted and perfusion weighted MR imaging

Late temporal lobe necrosis is a well-known and serious complication in patients with nasopharyngeal carcinoma (NPC) following radiotherapy. Owing to the close proximity to the skull base, the medial temporal lobes are inevitably included in the target volume of irradiation. Patients with NPC provide a unique opportunity in study of delay radiation effect in normal human brain. The objective of this study was to evaluate late temporal lobe radiation injury by combined multi-section diffusion weighted and perfusion weighted MR imaging. We prospectively studied 16 patients with typical clinical symptoms of late temporal lobe necrosis or other abnormalities in the temporal lobes incidentally detected by conventional MR imaging. All patients had a previous history of radiotherapy for histologically proven NPC. Conventional T1- and T2-weighted images, fast gradient echo with echo-planar diffusion-weighted and perfusion-weighted MR imaging were performed. Apparent diffusion coefficient (ADC) map and relative cerebral blood volume (rCBV) map were computed via commercially available software. MR diffusion and perfusion images were then analyzed and graded by two independent observers with focusing on the diffusion and perfusion mismatch. The temporal lobe lesions displayed marked high diffusion on the ADC map. The rCBV map also revealed marked hypoperfusion in these temporal lobe lesions in all patients. The areas of abnormality on the rCBV map were significantly larger than the lesions on the ADC map in 14 patients (observer 1) and 13 patients (observer 2). Since late temporal lobe necrosis is probably caused by damage of the endothelium of vessels and ischemia, perfusion and diffusion mismatch might imply injured tissue but potentially salvageable brain tissue. A mismatch may be potentially used to predict the response to treatment in-patients with late temporal lobe necrosis.

CT and MRI in the Diagnosis of Acute Stroke and Their Role in Thrombolysis

Thrombolysis is an effective but potential deleterious therapy and should therefore be limited to patients with acute intracerebral vessel occlusion and salvageable tissue. MRI currently develops towards the new diagnostic standard for the selection of stroke patients eligible for acute thrombolytic treatment and acute stroke studies. Diffusion- and perfusion-weighed MRI provides diagnostic information not available from the neurological assessments or from CCT and conventional spin-echo MRI. As high-speed DWI and PWI protocols become standardized, a 15-minute integrated stroke protocol of employing echo-planar imaging (EPI) can be outinely performed in the setting of acute clinical stroke. The combination of these MR techniques is suitable to define tissue at risk of infarction that is potentially salvageable brain tissue (an estimate of the ischemic penumbra) and may respond to early recanalization even beyond 3 hours after stroke onset. The extension of the therapeutic window for thrombolytic therapy towards 6 hours in a subpopulation of acute stroke patients might open the way for the successful reperfusion therapy in more stroke patients.

Magnetic resonance prediction of outcome after thrombolytic treatment

Treatment of clinical stroke with recombinant tissue plasminogen activator (rt-PA) carries the risk of hemorrhagic complications. Hence, predictors of therapeutic outcome with respect to (a) reperfusion and (b) tissue recovery would be very useful to identify potentially salvageable brain tissue. Magnetic resonance (MR) parameters, especially the apparent diffusion coefficient of water (ADC), perfusion-weighted imaging (PWI) and T2 relaxometry are thought to provide this information. We evaluated the prognostic implications of ADC, PWI and T2 relaxometry immediately before initiation of thrombolytic treatment in a model of clot embolism in rats. Animals (n = 14) were treated with intraarterial rt-PA (10 mg/kg) at 90 min after embolism. MR imaging was repeatedly performed at 4.7 T before and up to 5.5 h after embolism. ADC was calculated from diffusion-weighted images (b-values: 30, 765, 1500 s/mm2), arterial spin tagging was used for PWI, and quantitative T2 relaxometry was performed with a Carr-Purcell-Meiboom-Gill (CPMG) sequence. A reperfusion index was calculated to assess the quality of thrombolytic recanalization. The decline of ADC at the end of the experiment to below 80% of control was defined as unfavorable outcome. The probability of tissue injury at the end of the experiments increased with the severity of ADC changes before the initiation of treatment (probability of unfavorable outcome: 21%, 44%, 65% for ADC values of 80–90%, 70–80% and <70% of control, respectively). Pretreatment PWI or T2 relaxometry also correlated with outcome but—alone or in combination with pretreatment ADC maps—did not improve injury prediction over that obtained by ADC alone. Outcome was influenced positively by successful reperfusion the quality of which, however, could not be predicted by pre-treatment MR characteristics. The data demonstrate that ADC mapping performed before the initiation of thrombolytic treatment provides reliable risk assessment of impeding brain injury but due to uncertainties of postischemic reperfusion does not allow precise outcome prediction in individual experiments.

Albumin or Hetastarch Improves Neurological Outcome and Decreases Volume of Brain Tissue Necrosis But Not Brain Edema Following Closed-Head Trauma in Rats

The present study examined whether hemodilution with 20% human serum albumin (HSA) or 10% hydroxyethyl starch (HES) improved the outcome from closed-head trauma (CHT) in rats. Rats anesthetized with halothane were given one of three hemodilution solutions (i.e., 20% HSA, 10% HES, or control [0.9% saline]) after CHT or sham surgery. CHT was delivered using a weight drop impact of 0.5 J onto the closed cranium. The hemodilution solution (volume = 1% of body weight) was given just after determining the neurological severity score (NSS) at 1 hour following CHT. The NSS was determined again at 24, 48, and 72 hours following CHT. At 72 hours, brains were removed, and brain edema and brain tissue necrosis volume were determined. Solutions of 20% HSA and 10% HES significantly improved brain tissue necrosis volume (143 +/- 72 mm3 and 104 +/- 53 mm3 as compared to 271 +/- 65 mm3 in controls, mean +/- SD) and NSS (12 +/- 2 and 9 +/- 2 as compared to 15 +/- 2 in controls at 72 hours, median +/- range) but not brain edema. The hematocrit decreased similarly in all groups during hemodilution. Hemodilution with 20% HSA and 10% HES following CHT in rats did not decrease brain edema but did decrease brain tissue necrosis volume and NSS (improved neurological function), suggesting that the beneficial effect of hemodilution resulted not from decreased edema formation but rather from effects not measured in this study such as improved perfusion of the salvageable brain tissue surrounding the core injury.

Expanding the window for thrombolytic therapy in acute stroke. The potential role of acute MRI for patient selection.

Effective therapy was not available for treatment of acute stroke until 1995, when tissue plasminogen activator (tPA) was shown to improve neurological and functional outcome in stroke patients who were treated within 3 hours of symptom onset. Currently, many patients do not qualify for tPA therapy because they present for evaluation beyond 3 hours after stroke onset. Attempts to expand the treatment window to 6 hours, using CT to select patients, have failed. Use of early MR imaging may provide significant advantages over CT for identification of patients who are likely to benefit from thrombolytic therapy because (1) the early perfusion-weighted imaging (PWI) lesion estimates the region of acute dysfunctional brain tissue, whereas the acute diffusion-weighted imaging (DWI) lesion appears to correspond to the core of the early infarction; (2) the mismatch between the acute PWI lesion and the smaller DWI lesion represents potentially salvageable brain tissue (an estimate of the ischemic penumbra); and (3) in patients with a PWI/DWI mismatch, early reperfusion is often associated with substantial clinical improvement and reversal or reduction of DWI lesion growth. Clinical trials that use new MRI techniques to screen patients may be able to identify a subset of acute stroke patients who are ideal candidates for thrombolytic therapy even beyond 3 hours after stroke onset.

Cerebral blood volume in acute brain infarction: A combined study with dynamic susceptibility contrast MRI and 99mTc-HMPAO-SPECT.

The aim of this study was to correlate the abnormality in cerebral blood volume (CBV) measured by dynamic susceptibility contrast-enhanced MRI with that in cerebral blood flow (CBF) estimated by single-photon emission CT with [99mTc]hexamethylpropylenamine-oxime in patients with acute ischemic stroke. Nine patients with unilateral occlusion of either the middle cerebral artery or the internal carotid artery (4 men and 5 women; mean+/-SD age, 74.4+/-11.6 years) were studied within 6 hours after stroke onset. The relative CBV (relCBV) and CBF (relCBF) in the lesions were defined relative to the contralateral mirror regions. In the brain regions with mild (relCBF >/=0.60), moderate (0.40</=relCBF<0.60), and severe (relCBF <0.40) hypoperfusion, the mean relCBV values were 1.29+/-0.31, 0.94+/-0.49, and 0.30+/-0.22, respectively. The relCBV was significantly elevated in the brain areas with mild hypoperfusion (P<0.001) and significantly reduced in the brain areas with severe hypoperfusion (P<0.001). The relCBF was significantly better than the relCBV in predicting the evolution of infarction (P<0.02). The probability of evolving infarction for the hypervolemic (relCBV >1.0) regions was significantly lower than that for hypovolemic (relCBV <1.0) regions in the relCBF range between 0.40 and 0.50 (P<0.02). In acute ischemic stroke within 6 hours of onset the CBV can be either increased, normal, or decreased, depending on the severity of hypoperfusion. The increased CBV has a protective effect on evolving infarction. Although the CBF is a better predictor of tissue outcome, the CBV measurement may help detect potentially salvageable brain tissue in the penumbra with compromised blood flow.

Neuroprotection in acute ischaemic stroke. Current status and future potential.

Acute ischaemic strokes can potentially be treated by 2 different mechanisms: lysing the thrombus to enhance brain perfusion or salvaging brain tissue directly. Neuroprotective agents are designed to try to salvage brain tissue. They work either during acute ischaemia or during reperfusion, when additional brain injury may occur. Despite the completion of a number of clinical trials investigating neuroprotective agents that have various mechanisms of action, as yet no effective agent has been identified. Some drugs, such as N-methyl-D-aspartate (NMDA) receptor antagonists and anti-leucocyte adhesion agents, have been limited by adverse effects and drug reactions. However, the development of other agents in these classes that have better risk to benefit ratios may lead to an effective neuroprotective drug. Other drugs, including citicoline, clomethiazole and nalmefene, have more efficacy in certain patient subgroups than in the stroke population as a whole. Therefore, targeting these agents toward the groups in which they are most likely to work, such as patients with a certain size of stroke, may uncover efficacy. Encouragingly, a number of drugs that are in the early stages of development, such as YM 872, Bay X 3702 and BMS 204352, appear to offer new hope for neuroprotection.