Background: It has been 50 years since the first explorations of the physiology of cerebral ischemia by measuring cerebral blood flow (CBF), and 25 years since the approval of tissue plasminogen activator for treating acute ischemic stroke. My personal career began and matured during those eras. Here, I provide my perspective on the evolution of acute stroke research and treatment from 1971 to the present, with some in-depth discussion of the National Institutes of Neurologic Disease and Stroke (NINDS) tissue-type plasminogen activator (tPA) stroke trial and development of mobile stroke units. Summary: Studies of CBF and metabolism in acute stroke patients revealed graded tissue injury that was dependent on the duration of ischemia. Subsequent animal research unraveled the biochemical cascade of events occurring at the cellular level after cerebral ischemia. After a decade of failed translation, the development of a relatively safe thrombolytic allowed us to achieve reperfusion and apply the lessons from earlier research to achieve positive clinical results. The successful conduct of the NINDS tPA stroke study coupled with positive outcomes from companion tPA studies around the world created the specialty of vascular neurology. This was followed by an avalanche of research in imaging, a focus on enhancing reperfusion through thrombectomy, and improving delivery of faster treatment culminating in mobile stroke units. Key Messages: The last half century has seen the birth and evolution of successful acute stroke treatment. More research is needed in developing new drugs and catheters to build on the advances we have already made with reperfusion and also in evolving our systems of care to get more patients treated more quickly in the prehospital setting. The history of stroke treatment over the last 50 years exemplifies that medical “science” is an evolving discipline worth an entire career’s dedication. What was impossible 50 years ago is today’s standard of care, what we claim as dogma today will be laughed at a decade from now, and what appears currently impossible will be tomorrow’s realities.
Hemicraniectomy (HC) is a proven treatment to reduce mortality and improve outcomes in patients with malignant middle cerebral artery (MCA) infarction. The benefit of HC in patients with MCA strokes plus infarctions in other vascular territories has not been well defined. We hypothesized that there would be no difference in outcomes in patients with MCA strokes compared to those with MCA Plus infarctions. We retrospectively reviewed our registry from 07/2003 to 12/2011, and identified consecutive patients diagnosed with an ischemic stroke that underwent HC. Outcome measures included mRS at discharge, mRS at day 90 and death at one year. A good outcome was defined as mRS 0-4. The vascular territory of infarction was established by a vascular neurologist who reviewed the nearest CT scan prior to the procedure and compared it with the official interpretation of a neuroradiologist. The MCA Plus infarctions included MCA + anterior cerebral artery (ACA), MCA + posterior cerebral artery (PCA) and MCA + ACA + PCA. Ninety seven patients had a HC. Sixty four were MCA and 33 were MCA Plus. The mean MCA and MCA plus ages were 51.9 (± 14.2) and 51.3 (± 12.8) years respectively. Median NIHSS was 12.5 (IQR 10.0-15.0) in MCA vs. 12.2 (IQR 9.5-14.0) in MCA Plus. MCA group had a good outcome at discharge in 25% of subjects vs. 21% in the MCA Plus cohort, OR 0.72 (95% CI: 0.24-2.15). For patients with available data, 40% of MCA was dead at 90 days and 50% in MCA Plus, and for those who survived, 33% of MCA had a good outcome compared to 15% of the MCA Plus, OR 2.4 (95% CI: 0.45-7.61). Forty eight percent of MCA patients were dead at one year vs. 76% of the MCA Plus patients. We found no difference in good outcomes at discharge and 90 days in our cohort of patients who received a HC with MCA or MCA plus infarctions. Limitations include a high rate of missing data at day 90 and at one year, and poor standardization of HC timing. Further prospective studies are necessary to evaluate the clinical implications of HC in MCA Plus syndromes.
Background Bone marrow mononuclear cells (MNC) represent an investigational treatment for stroke. The objective of this study was to determine the relevance of vasoactive mediators, generated in response to MNC injection, as factors regulating cerebral perfusion (CP), the biodistribution of MNC, and outcome in stroke. Methods Long Evans rats underwent transient middle cerebral artery occlusion. MNC were extracted from the bone marrow at 22 hrs and injected via the internal carotid artery or the femoral vein 2 hours later. CP was measured with MRI or continuous laser Doppler flowmetry. Serum samples were collected to measure vasoactive mediators. Animals were treated with the Nitric Oxide (NO) inhibitor, L-NAME, to establish the relevance of NO-signaling to the effect of MNC. Lesion size, MNC biodistribution, and neurological deficits were assessed. Results CP transiently increased in the peri-infarct region within 30 min after injecting MNC compared to saline or fibroblast control. This CP increase corresponded temporarily to serum NO elevation and was abolished by L-NAME. Pre-treatment with L-NAME reduced brain penetration of MNC and prevented MNC from reducing infarct lesion size and neurological deficits. Conclusions NO generation in response to MNC may represent a mechanism underlying how MNC enter the brain, reduce lesion size, and improve outcome in ischemic stroke.
Subcortical strokes (SCS) are associated with stroke progression. The primary objective was to assess the incidences of neurological deterioration and its spontaneous reversal in SCS patients. We also estimated the risk of poor outcome associated with deterioration. Methodology: A prospective cohort of SCS patients was enrolled based on clinical exam and imaging studies, and was followed through the course of hospitalization. NIH stroke scale (NIHSS) assessments were performed daily and whenever symptoms worsened (increase of ≥ 1 in motor scale). Modified Rankin Scale (mRS) score at discharge was used to assess outcomes. Patients received standard of care stroke therapy including IV t-PA as per AHA guidelines, and episodes of deterioration were managed conservatively. The Anderson Gill Cox proportional hazard model was used to analyze factors associated with time to deterioration and spontaneous reversal. Log binomial regression was performed for estimation of risk of poor outcome. Results: The cumulative incidence of deterioration was 43.3% and of those who deteriorated, spontaneous reversal occurred in 37.8%. The median time to deterioration was 21 hours from stroke onset. Use of IV t-PA was significantly associated with both deterioration (HR: 2.25, 95% CI: 1.13 - 4.49) (Figure 1a) and spontaneous reversal (HR: 4.36, 95% CI: 1.36 - 14.01) (Figure 1b). Deteriorated patients had a higher risk of poor discharge outcome (mRS ≥ 3) (RR: 1.80, 95% CI: 1.71 - 1.93), after adjusting for age, initial stroke severity, and use of IV t-PA. Conclusion: The results from this study establish a natural history of neurofluctuation in patients with SCS. Our data suggests that deterioration occurs early in these patients, and only about a third of deteriorated patients reverse spontaneously. Furthermore, deterioration is associated with poor short term functional outcome. There is a need to develop and test novel therapies to treat neurological deterioration in SCS.
In Response:We thank Dr Shah for his interest and insightful comments on our randomized trial of adjunctive argatroban administered to recombinant tissue plasminogen activator (r-tPA)-treated patients with stroke (ARTSS-2 [Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke]). 1 Compared with r-tPA alone, ARTSS-2 demonstrated safety and improved clinical outcomes in patients who received combination r-tPA and argatroban.In general, we are in complete agreement with Dr Shah's comments and would like to make the following points.Dr Shah correctly points out our hypothesis that adjunctive argatroban enhances recanalization of proximal, large vessel occlusions.Although our current study did not show increased recanalization of large vessel occlusions, it was underpowered to do so.Previous data suggested an effect of argatroban on increasing recanalization.For example, animal models of embolic stroke found enhanced lysis with r-tPA+argatroban, and patients with acute myocardial infarction had substantially higher rates of complete reperfusion in argatroban+r-tPA compared with intravenous-heparin+r-tPA (57% versus 20%; P=0.03) with lower rates of major hemorrhage. 2,3ur pilot study suggested greater 2-hour recanalization rates in argatroban+r-tPA compared with historical r-tPA-alone controls. 4ast, other explanations remain plausible, such as clot burden and location, as well as the early timing of follow-up imaging.We agree with Dr Shah's comment on distal vascular patency via thrombin inhibition.We did not study reperfusion in the microcirculation, which also may be the location of some of argatroban's benefit.Even in light of these considerations and the possibility of argatroban's benefit on reperfusion, we agree with Dr Shah that the drug may also have a neuroprotective effect as referenced in his letter.Therefore, argatroban's inhibition of thrombin's neurotoxic effects definitely warrants further study.To that end, we have proposed a large randomized trial of argatroban+r-tPA embedded in the MOST trial (Multi-arm Optimization of Stroke Thrombolysis).If funded, this study, which will have a wider scope by not being limited only to patients with large vessel occlusions, will not address mechanism but should detect a beneficial clinical effect from whatever method argatroban adds to r-tPA.
To provide data to guide physicians and family when deciding whether a patient should be electively intubated after ischemic stroke.Chart review and patient interview. Clinical course, neurologic outcome, and financial and psychosocial effect of the decision to intubate were determined.Neurology/Neurosurgery critical care unit.Of our last 250 acute carotid territory ischemic stroke cases, we found 20 patients (8%) who were electively intubated, after CT and neurologic assessment, for neurologic deterioration.All patients received standard medical therapy.Intubation occurred 3 hours to 7 days (mean, 41 hours) after the onset of symptoms; six of 20 patients required intubation within the first 6 hours. Once clinical deterioration began, 10 of 20 patients required intubation within 1 hour. Six of 20 patients were discharged alive; two subsequently died, one is mostly dependent, two became mostly independent (one of these had a hemicraniectomy and is still improving, and the other died of an intercurrent illness 4 years after her stroke), and one is totally independent. The four "good" outcome survivors were distinguished by higher Glasgow Coma Scale scores (9.2 versus 5.9), and extubation was usually possible within 72 hours. For nonsurvivors, mean hospitalization after intubation was 6.4 days. In survivors, the monthly uninsured cost was $0 to $2,000, and caregivers experienced moderate stress. The same decision would be repeated by 76% of caregivers; 53% of caregivers would want intubation for themselves.Satisfactory outcome is possible in the 8% of ischemic stroke patients requiring elective intubation. Possible predictors of good outcome include less severe depression of consciousness at the time of intubation, extubation within 3 days, and hemicraniectomy. In retrospect, most families would repeat the decision to intubate. Further study in more patients of the cost/benefit of cerebral resuscitation after stroke is greatly needed.
ntravenous tissue plasminogen activator (rt-PA) remains the only approved therapy for acute ischemic stroke with demonstrated effectiveness in phase 3 clinical trials. 1 Unfortunately, the utilization of this treatment is limited by a 6% risk of symptomatic brain hemorrhage 2 and a brief 3-hour time window of efficacy from symptom onset to treatment. 3Furthermore, its effectiveness is limited for several reasons; intravenously administered rt-PA often fails to lyse large clots, 4,5 arteries reocclude in about a third of cases, 5 flow may remain stagnant in the microcirculation despite clot lysis, 6,7 and cellular injury may continue despite reperfusion.
Introduction: Randomized clinical trials have demonstrated efficacy and safety of endovascular thrombectomy (EVT) among patients presenting up to 24 hours of last known well (LKW). Recent reports have suggested EVT could result in better functional outcomes with acceptable risk profile even in patients presenting beyond 24 hours of LKW, but exploration of the role of EVT in elderly patients presenting beyond 24 hours is limited. Methods: We aimed to evaluate functional and safety outcomes for EVT in patients with age ≥80y with a large vessel occlusion (LVO) beyond 24 hours of LKW, from a pooled, international cohort (17 centers across US, Spain, Australia and New Zealand) between 7/2012 and 12/2021. Primary outcome was a shift on modified Rankin Scale score at 90-day follow-up. Results: Of 301 included, 88 (53 EVT, 35 medical management MM) were aged ≥80y, with 57 females and 21 nonagenarians. Median(IQR) NIHSS - 17.5 (11-22),CT ASPECTS - 7(4-9), ischemic core 5.5 (0-26) ml. Overall, as age increased, clinical outcomes worsened (acOR: 0.64, 95% CI: 0.55-0.74, p<0.001 per 10 year increment). However, EVT was associated with a shift towards better functional outcome among patients with age≥80y (acOR: 8.31, 95% CI:2.80-24.68, p<0.001) and among patients with age<80y (acOR: 2.11, 95% CI: 1.22-3.66, p=0.008), with a significant interaction (p-int:0.047 – fig1) suggesting higher improvement within octogenarians. Estimates of Functional independence (EVT: 27% vs MM: 6%, aOR: 11.86, 95% CI: 1.75-80.28, p=0.011) and mortality (EVT: 42% vs MM: 71%, aOR: 0.16, 95% CI: 0.05-0.52, p=0.003) also favored EVT, with similar results obtained using inverse probability of treatment weights [Table 1]. 4 patients within EVT arm and no patients within MM arm developed symptomatic ICH. Among octogenarians receiving EVT, lower presentation NIHSS (aOR: 0.77, 95% CI: 0.64-0.92, p=0.003 per point increment) and presence of M2 occlusion (aOR: 11.01, 95% CI: 1.15-105.36, p=0.037 were independently associated with functional independence at 90-day follow-up), but not time to procedure (aOR: 0.99, 95% CI: 0.96-1.02, p=0.64, fig2). Conclusions: In a pooled international cohort of octogenarians who presented beyond 24 hours with an LVO, EVT was associated with better functional outcomes, higher functional independence and lower mortality. Lower stroke severity and presence of M2 occlusion were independently associated with functional independence at 90-day after EVT.
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