María Alonso de Leciñana

Cerebral ischemia: from animal studies to clinical practice. Should the methods be reviewed?

The development of experimental models of focal cerebral ischemia has allowed for a better knowledge of its pathophysiology and for testing therapeutic strategies. However, most neuroprotective substances giving favorable results in these models have later not been shown to be clinically effective. This could be explained by several reasons. First, the homogeneity obtained in animal models in order to achieve results is not seen in clinical practice in humans, in whom a given pathological condition may show a high variability depending on several parameters. This makes it difficult to achieve groups of patients sufficiently large and homogeneous to obtain valid conclusions in the clinical trials. The lack of agreement between the experimental studies and the clinical practice can also be explained by other reasons, such as the methods of the experimental model itself; by the fact that the methods to assess results in these models are not comparable to those used in clinical practice; by pathophysiological differences between experimental animals and man, and even by the fact that the substances tested have different pharmacological properties in the different species. These disadvantages must not invalidate preclinical neuroprotection studies. Rather, the knowledge of the reasons for divergences with the clinical situation can help to optimize experimental models so that both become actually comparable, and the laboratory results can be confirmed by clinical studies.

Stroke mimics treated with thrombolysis: further evidence on safety and distinctive clinical features.

Background: Patients who present with symptoms mimicking ischaemic stroke (IS), but have a different diagnosis, are known as stroke mimics (SM). The necessity for rapid administration of intravenous thrombolysis in patients with acute IS may lead to treatment of patients with conditions mimicking stroke. A variable proportion of patients with SM (1.4–14%) are currently treated with intravenous tissue plasminogen activator therapy (IV-tPA). The outcome of these patients is generally favourable and complications are rather infrequent. We aimed to determine the frequency, clinical features and prognosis of SM patients treated with IV-tPA in an experienced stroke centre. Methods: A prospective registry was assembled with patients treated with IV-tPA at our stroke unit from January 2004 to December 2011. We recorded age, gender, baseline National Institutes of Health Stroke Scale (NIHSS) score, treatment delay, vascular risk factors, clinical syndrome and aetiology. We retrospectively analysed the clinical characteristics of SM, safety (symptomatic intracranial haemorrhage and mortality) and outcome measures (modified Rankin Scale at 3 months, mRS) and compared them with IS patients. Results: 621 patients were treated with IV-tPA during the study period, 606 (97.5%) were IS and 15 (2.4%) were SM. The aetiology of SM was somatoform disorders (5), headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) syndrome (3), herpetic encephalitis (2), glial tumours (2), and migraine with aura, focal seizure and cortical vein thrombosis in single cases. SM were younger (72 ± 14 vs. 53.7 ± 16 years, p < 0.05), had a lower baseline deficit [NIHSS 13 (9–18) vs. 8 (5–10), p < 0.05], fewer vascular risk factors, and left hemisphere symptoms were predominant (80 vs. 52.4%, p < 0.05). Global aphasia without hemiparesis (GAWH) was the presenting symptom in 8 (54%) SM and 44 (7%) IS (p < 0.05). Multimodal computed tomography was performed in 3 SM patients and showed perfusion deficits in 2 of them. No intracranial haemorrhage or disability (functional outcome at 3 months, mRS >2) was recorded in any SM patient. Conclusions: The use of intravenous thrombolysis appears to be safe in our SM patients, and prognosis is universally favourable. Somatoform disorder and HaNDL syndrome were prominent causes, and GAWH the most common presentation. The safety of thrombolysis in SM suggests that delaying or withholding treatment may be inappropriate: the benefit of thrombolysis in case of IS may outweigh the risks of treating an SM. Further studies may assess the future role of multimodal computed tomography in the differential diagnosis between IS and SM.

Cerebral Protection, Brain Repair, Plasticity and Cell Therapy in Ischemic Stroke

Among available treatments in the acute ischemic stroke, only intravenous thrombolysis has been demonstrated to be efficacious. Although the majority of pharmacological neuroprotectants have been efficacious in experimental studies, they have failed in clinical trials. Hence, we need to consider integrated cerebral protection which includes the concept of cerebral repair by supporting cerebral plasticity. We provide a nonsystematic review of the studies published on cerebral protection and repair treatments of cerebral ischemia considering the possibilities of stimulating brain plasticity by trophic factors and cell therapy. The majority of the neuroprotective drugs have failed in clinical trials. Citicoline shows a benefit in meta-analysis and it is currently being explored in a new trial (ICTUS). Neuroprotective drugs combined with reperfusion offer favorable results in experimental animals, but data from clinical studies are not enough. Repair therapies using cerebral plasticity stimulation (trophic factors) and cell therapy have shown certain efficacy in experimental and clinical studies and they are a developing route with clinical therapeutic perspectives.

Estrogens as neuroprotectants against ischemic stroke.

Estrogens have proven vasoprotective properties against atherosclerosis that depend on the direct effect on vascular smooth muscle and endothelium and on systemic actions that imply serum lipids, coagulation and fibrinolytic cascades, vasoactive proteins and antioxidant systems. They also have neuroprotective effects against cerebral ischemia that include antioxidant and anti-inflammatory effects, modulation of protein synthesis, inhibition of apoptosis and trophic effects and preservation of microvascular blood flow in the ischemic area. Estrogenic actions depend on activation of specific estrogen receptors that modulate gene expression and produce long-term effects on vascular endothelial and smooth muscle cells, neurons and glia, on interaction with plasma membrane sites that produce rapid non-genomic actions and also on receptor-independent mechanisms. This paper reviews what it is known about the mechanisms underlying the vaso- and neuroprotective effects of estrogens. Experimental and clinical evidences of such protective effects are also discussed. Therapeutical implications for stroke prevention and treatment derived from the available evidence are considered.

Futile Interhospital Transfer for Endovascular Treatment in Acute Ischemic Stroke The Madrid Stroke Network Experience

Background and Purpose— The complexity of endovascular revascularization treatment (ERT) in acute ischemic stroke and the small number of patients eligible for treatment justify the development of stroke center networks with interhospital patient transfers. However, this approach might result in futile transfers (ie, the transfer of patients who ultimately do not undergo ERT). Our aim was to analyze the frequency of these futile transfers and the reasons for discarding ERT and to identify the possible associated factors. Methods— We analyzed an observational prospective ERT registry from a stroke collaboration ERT network consisting of 3 hospitals. There were interhospital transfers from the first attending hospital to the on-call ERT center for the patients for whom this therapy was indicated, either primarily or after intravenous thrombolysis (drip and shift). Results— The ERT protocol was activated for 199 patients, 129 of whom underwent ERT (64.8%). A total of 120 (60.3%) patients required a hospital transfer, 50 of whom (41%) ultimately did not undergo ERT. There were no differences in their baseline characteristics, the times from stroke onset, or in the delays in interhospital transfers between the transferred patients who were treated and those who were not treated. The main reasons for rejecting ERT after the interhospital transfer were clinical improvement/arterial recanalization (48%) and neuroimaging criteria (32%). Conclusions— Forty-one percent of the ERT transfers were futile, but none of the baseline patient characteristics predicted this result. Futility could be reduced if repetition of unnecessary diagnostic tests was avoided.

Safety and Outcomes following Thrombolytic Treatment in Stroke Patients Who Had Received Prior Treatment with Anticoagulants

Background: Information is scare regarding the safety of intravenous thrombolysis in patients under anticoagulant treatment, given that this is an exclusion criterion in clinical trials. We analyzed the risk of hemorrhagic complications following thrombolysis in patients under treatment with low-molecular-weight heparins (LMWH) and oral anticoagulants (OA). Methods: In a multicentered prospective study of consecutive acute stroke patients treated with intravenous alteplase we recorded age, gender, baseline NIHSS score, treatment delay, risk factors, etiology and previous therapy. The neurological progress (National Institutes of Health Stroke Scale at 7 days) and functional evolution at 3 months (modified Rankin Scale score), mortality and symptomatic intracerebral hemorrhage (SICH) were compared between patients with LMWH or OA and those without prior anticoagulant therapy. Results: Of the 1,482 patients, 21 (1.4%) had received LMWH and 70 (4.7%) OA (international normalized ratio, INR, 0.9-2.0). Patients on OA were older, presented higher basal glucose levels, had been treated later and had a higher prevalence of hypertension, dyslipidemia, prior stroke, atrial fibrillation and cardioembolic pathologies. The severity of stroke on admission was similar in the different groups. The percentages of patients achieving independence (mRS 0-2) at 3 months were 33, 44 and 58 (LMWH, OA and no prior anticoagulant treatment, respectively; p = 0.02 for both comparisons of LMWH vs. no treatment and OA vs. no treatment); the mortality rates were 30, 25 and 12% (p = 0.010, p = 0.001, respectively) and the SICH were 14, 3 and 2% (p < 0.0001 for comparison of LMWH vs. no treatment). In the case of treatment with OA, the outcomes were independent of the INR value. Following adjustment for confounding variables, the prior use of OA was associated with higher mortality (OR: 2.15, 95% CI: 1.1-4.2; p = 0.026) but not with SICH transformation or lower probability of independence. The use of LMWH was associated with higher mortality (OR: 5.3, 95% CI: 1.8-15.5; p = 0.002), risk of SICH (OR: 8.4, 95% CI: 2.2-32.2; p = 0.002) and lower probability of achieving independence (OR: 0.3, 95% CI: 0.1-0.97; p = 0.043). Conclusions: The use of intravenous thrombolysis appears to be safe in patients previously treated with OA with INR levels <2 since there is no increase in SICH. The prior use of LMWH appears to increase the risk of SICH, death and dependence and, as such, the decision for systemic treatment with thrombolytic agents needs to be taken with caution in these cases. Larger case series are necessary to confirm these findings.

Benefits of intravenous thrombolysis in acute ischemic stroke related to extra cranial internal carotid dissection. Dream or reality

Background Small clinical series have reported the safety of intravenous thrombolysis in ischemic stroke related to extracranial internal carotid dissection. However, no studies specifically analyzing the effects on stroke outcome are available. Aims Our goal was to evaluate whether patients with ischemic stroke related to extracranial internal carotid dissection obtain any benefit from intravenous thrombolysis. Methods Multicenter, prospective and observational study conducted in four university hospitals from the Madrid Stroke Network. Consecutive ischemic stroke patients who received intravenous thrombolysis were included, as well as patients with extracranial internal carotid dissection regardless of intravenous thrombolysis treatment. Stroke severity (NIHSS) and three-month outcome (modified Rankin Scale) were compared between the following groups: (1) intravenous thrombolysis-treated patients with ischemic stroke related to extracranial internal carotid dissection vs. other causes of stroke; (2) intravenous thrombolysis-treated extracranial internal carotid dissection patients vs. nonintravenous thrombolysis treated. Outcome was rated at three-months using the modified Rankin Scale. A good outcome was defined as a modified Rankin Scale score ≤2. Results A total of 625 intravenous thrombolysis-treated patients were included; 16 (2·56%) had extracranial internal carotid dissection. Besides, 27 patients with extracranial internal carotid dissection and ischemic stroke who did not receive intravenous thrombolysis were also included. As compared with other etiologies, patients with extracranial internal carotid dissection were younger, had similar stroke severity and showed less improvement in their NIHSS score at Day 7 (1·38; (95% CI −3·77 to 6·54) vs. 6·81; (95% CI −5·99 to 7·63) P=0·004), but without differences in good outcomes at three-months (43·8% vs. 58·2%; NS). Extracranial internal carotid dissection intravenous thrombolysis-treated patients had more severe strokes at admission than those who were nonintravenous thrombolysis treated (median NIHSS: 15 vs. 7; P=0·031). Intravenous thrombolysis was safe in extracranial internal carotid dissection with no symptomatic hemorrhagic events; however, without differences in good outcome compared with the natural course of extracranial internal carotid dissection (nonintravenous thrombolysis treated) after adjustment for stroke severity (46·7% vs. 64·3%; NS). Conclusions As compared with other etiologies, stroke due to extracranial internal carotid dissection seems to obtain similar benefits from intravenous thrombolysis in outcome at three-months. Although intravenous thrombolysis is safe in stroke attributable to extracranial internal carotid dissection, no differences in outcome were found when comparing intravenous thrombolysis treated with nonintravenous thrombolysis-treated patients, even after adjustment for stroke severity.

Microbleed Burden and Hematoma Expansion in Acute Intracerebral Hemorrhage

Background: Intracranial amyloid and hypertensive angiopathy have been related to impaired blood vessel function and the etiology of intracerebral hemorrhage (ICH). Microbleeds (MBs) are surrogate radiological markers that are associated with these underlying angiopathies. We assessed the hypothesis that MBs are associated with hematoma expansion (HE) in patients with hyperacute ICH. Methods: We studied patients with spontaneous supratentorial ICH within the first 6 h after onset. HE was defined as an increase ≥33% in the volume of hematoma on the follow-up CT in comparison with the admission CT. The volume was calculated using the ABC/2 formula. MBs were detected by specific magnetic resonance sequences (gradient-echo). The presence, number and distribution of MBs were analyzed. Results: Our study included 44 patients. Their mean age was 68.9 ± 11.1 years, and 70.5% of them were men. HE was observed in 14 of the patients (31.8%). HE was more prevalent in patients with more than 10 MBs compared with patients with 1-10 MBs (60 vs 12.5%; p = 0.03). Conclusion: A high burden of MBs is associated with an increased risk of HE in patients with ICH. This is probably a marker of a more severe underlying angiopathy.

New Goals in Ischemic Stroke Therapy: The Experimental Approach – Harmonizing Science with Practice

Undeniable advances have been made in clinical and experimental investigation into the pathophysiology, diagnosis, and treatment of cerebral ischemia. However, with the exception of intravenous thrombolysis and some neuroprotectors, such as citicoline, the majority of the drugs successfully tested in experimental studies have failed in clinical trials. Valuable lessons for the improvement of research methodology and appropriate coordination of experimental and clinical research can be learnt from the analysis of discrepancies between the laboratory and clinic, which will allow us to increase the power and cost-effectiveness of the studies. In addition, this progress has opened the way for the investigation of very promising new therapeutic strategies, such as combined pharmacological and mechanical thrombolysis, thrombolysis and neuroprotection, or the combination of various neuroprotectors, antiapoptotic therapies, and neurorestoration therapies, such as stem cell transplants.

Thrombolytic therapy for acute ischemic stroke after recent transient ischemic attack.

Background and aim Safety and efficacy of intravenous thrombolysis in stroke patients with recent transient ischemic attack are hotly debated. Patients suffering transient ischemic attack may present with diffusion-weighted imaging lesions, and although normal computed tomography would not preclude thrombolysis, the concern is that they may be at higher risk for hemorrhage ***post-thrombolysis treatment. Prior ipsilateral transient ischemic attack might provide protection due to ischemic preconditioning. We assessed post-thrombolysis outcomes in stroke patients who had prior transient ischemic attack. Methods Multicentered prospective study of consecutive acute stroke patients treated with intravenous tissue plasminogen activator (tPA). Ipsilateral transient ischemic attack, baseline characteristics, risk factors, etiology, and time-lapse to treatment were recorded. National Institutes of Health Stroke Scale at seven-days and modified Rankin Scale at three-months, symptomatic intracranial hemorrhage, and mortality were compared in patients with and without transient ischemic attack. Results There were 877 patients included, 60 (6.84%) had previous ipsilateral transient ischemic attack within ***one-month prior to the current stroke (65% in the previous 24 h). Transient ischemic attack patients were more frequently men (70% vs. 53%; P = 0.011), younger (63 vs. 71 years of age; P = 0.011), smokers (37% vs. 25%; P = 0.043), and with large vessel disease (40% vs. 25%; P = 0.011). Severity of stroke at onset was similar to those with and without prior transient ischemic attack (median National Institutes of Health Stroke Scale score 12 vs. 14 P = 0.134). Those with previous transient ischemic attack were treated earlier (117