Jay Shah, MD
Strecker J-K, Olk J, Hoppen M, Gess B, Diederich K, Schmidt A, et al. Combining Growth Factor and Bone Marrow Cell Therapy Induces Bleeding and Alters Immune Response After Stroke in Mice. Stroke. 2016
Cell-based therapies, such as transplantation of exogenous cells or stimulation of endogenous cells, for stroke are lacking. Bone marrow-derived cells (BMCs) are a viable option as they allow autologous transplantation and can be mobilized by granulocyte colony-stimulating factor (G-CSF). Cytokines released by BMCs contain neuroprotective properties and stimulate endogenous repair thereby potentially improving outcomes following ischemia. In this animal study, the authors’ hypothesis is that the combination of G-CSF and BMC is more effective than either single treatment in mice subjected to focal ischemia. There were 4 randomly assigned groups: placebo, G-CSF, BMC, and G-CSF and BMC. Ischemia was induced by occlusion of the middle cerebral artery for 30 minutes. Treatment occurred 90 minutes after ischemia induction. Rotarod and cylinder test were used to assess motor performance and forelimb activity, respectively. At 1 or 7 days after ischemia, brains were harvested to assess for ischemic damage by various techniques.
Jay Shah, MD
Alexander E. Merkler, MD
Rutten-Jacobs LCA, Traylor M, Adib-Samii P, Thijs V, Sudlow C, Rothwell PM, et al. Association of MTHFR C677T Genotype With Ischemic Stroke Is Confined to Cerebral Small Vessel Disease Subtype. Stroke. 2016
Discovering modifiable risk factors of ischemic stroke is the future of stroke prevention. Hyperhomocysteinemia is associated with an increased risk of stroke and the most common MHTFR mutation, the MHTFR C677T mutation, leads to increased levels of homocysteine. However, previous studies evaluating the effect of lowering homocysteine levels with B vitamins have been negative in terms of reducing overall stroke risk.
In the current manuscript, Dr. Rutten-Jacobs et al evaluate the association between the MHTFR C677T variant and small vessel disease. The authors evaluated the association between the MHTFR C677T mutation and both stroke subtype and white matter hyperintensity volume under the hypothesis that hyperhomocysteinemia only increases the risk of small vessel disease. In addition, as previous literature has shown an association between hypertension and homocysteine, the authors stratified patients by the presence of hypertension.
The authors identified 1359 cases of lacunar strokes, almost 4000 cases of large vessel and cardioembolic strokes and over 14 000 controls. The MHTFR C677T mutation was significantly associated with lacunar stroke and white matter hyperintensity volume, but not with other stroke subtypes. Furthermore, stratifying the lacunar strokes by hypertension status, confirmed the association the MHTFR C677T mutation with lacunar strokes in hypertensive, but not in normotensive patients.
The MHTFR C677T variant is associated with an elevated risk of specifically lacunar stroke and in patients who are hypertensive. The study adds further support that hyperhomocysteinemia is a risk factor for small vessel disease but not other subtypes of ischemic stroke. The manuscript should serve as a prime example of the importance of correctly choosing an outcome – perhaps B vitamins may successfully reduce stroke in patients with hyperhomocysteinemia when specifically lacunar stroke is chosen as the outcome of interest.
Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke
Hafez S, Abdelsaid M, El-Shafey S, Johnson MH, Fagan SC, Ergul A. Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke. Stroke. 2016
Hyperglycemia in the setting of acute ischemic stroke has been associated with worsened outcomes, with an association seen with worsened vascular injury, increased infarct size, and hemorrhagic transformation; however, the mechanisms through which this occurs is not well elucidated. Here, matrix metalloprotease 3 (MMP3), which has previously been shown to contribute to tPA induced hemorrhagic transformation, was identified as a possible mediator of injury in hyperglycemic stroke.
Russell Mitesh Cerejo, MD
Pasquini M, Benedictus MR, Boulouis G, Rossi C, Dequatre-Ponchelle N, Cordonnier C. Incident Cerebral Microbleeds in a Cohort of Intracerebral Hemorrhage. Stroke. 2016
The authors studied prognostic factors of incident cerebral microbleeds (CMBs) in the PITCH study primary intracerebral hemorrhage (ICH) cohort with at least 2 MRIs and survival for 6 months post event, stratifying the findings according to the index ICH location.
Amongst 168 included patients (median age 64 years) with ICH, 53% had at least 1 CMB.
Meta-Analysis Concludes Pregnancy is Relatively Safe in Patients With a History of Cerebral Venous Thrombosis
Cerebral venous thrombosis (CVT) is one of the most common causes of stroke during pregnancy and the puerperium, accounting for between one fourth and one half of all strokes during that period. Risk of CVT and other venous thrombotic events (VTEs) is increased during pregnancy, and women with a previous episode of non-cerebral VTE have a threefold to fourfold higher risk of VTE during subsequent pregnancies. Although thrombosis and thromboembolism is the leading cause of maternal mortality in developed countries, few studies have specifically investigated the safety of pregnancy in women with prior CVT. Aguiar de Sousa et al. performed a systematic review to ascertain the risk of CVT recurrence, occurrence of non-cerebral VTE, risk to the viability of pregnancy and the effect of antithrombotic prophylaxis.
It is unfortunate that the outcome that would have the potential to influence clinical practice (effect of antithrombotic prophylaxis) could not be adequately assessed due to the method of data collection in the studies reviewed. A larger study evaluating VTE, pregnancy outcomes and prophylaxis complications could be useful in this regard. Inconsistent and incomplete reporting of the etiology of the index CVT represents another gap in data reporting with the potential to influence clinical practice. Given that the two reported cases of recurrent CVT were present in patients with pre-existing prothrombotic states (Protein S deficiency and sickle-cell anemia, respectively), more thorough data collection in a larger study could aid clinicians in risk stratifying patients to identify those who may be suitable for more aggressive prophylactic measures.
Alexander E. Merkler, MD
Dubosh NM, Bellolio MF, Rabinstein AA, Edlow, JA. Sensitivity of Early Brain Computed Tomography to Exclude Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis. Stroke. 2016
Subarachnoid hemorrhage (SAH) is the most devastating type of stroke – 50% of survivors are dead within six months and among those patients who survive, only 50% return to their previous level of functioning. For decades, classic neurology dogma has stated that in order to rule out a SAH, any patient who presents with a thunderclap headache (HA) must receive a lumbar puncture (LP) if the head CT is negative. However, recent data suggests that in neurologically intact patients, a CT is 100% sensitive to rule out SAH when performed within six hours using a modern generation CT scanner (16-slice or greater). Hence, is there is no longer a need to perform an LP after a negative head CT that is performed within six hours of HA onset?
In this manuscript, Dr. Dubosh et al perform a meta-analysis to determine the sensitivity of modern generation CT scanners to rule out SAH in patients presenting to an emergency department within six hours of thunderclap HA. The authors identified five articles that met their inclusion criteria; four were retrospective and one was prospective. In total, 8,907 patients with thunderclap HA underwent a CT within six hours.
Overall, thirteen out of the 8,907 patients had a missed SAH. The overall sensitivity of CT was 0.987 (95% CI 0.971-0.994), specificity was 0.999 (95% CI 0.993-1.0) and the likelihood ratio of a negative CT was 0.010 (95% CI 0.003-0.034). This equated to a miss rate of 1.5 per 1000 patients who present with thunderclap HA and receive a modern CT scan within six hours.
It is important to note that each of the five studies had certain limitations. For example, perimesencephalic hemorrhage1 and SAH caused by a cervical arteriovenous malformation2 were considered missed causes of SAH. In addition, in the one prospective study by Perry et al3 (in which there were no documented missed cases of SAH), an LP was not performed in every patient who presented with thunderclap HA and had a negative CT. Although there was close follow-up using telephone interviews and monitoring coroner’s records, there may have been missed cases of SAH.
Modern CT performed within 6 hours of patients presenting with thunderclap HA is an extremely sensitive tool to rule-out SAH. As with most tests, it is impossible to say that it is 100% sensitive, but it certainly approaches it. Although perhaps very few cases of SAH may be missed, clinicians must weigh this against the potential consequences of performing an LP including time, anxiety, post-LP complications, unnecessary vascular imaging (CTA, MRA, angiography) and probably most importantly subsequent ramifications such as inappropriate procedures for incidentally found vascular lesions. Of course, missing a SAH may be life threatening and can lead to significant consequences including death.
1. Blok KM, Rinkel GJ, Majoie CB, Hendrikse J, Braaksma M, Tijssen CC et al. CT within 6 hours of headache onset to rule out subarachnoid hemorrhage in nonacademic hospitals. Neurology. 2015;12:1927-193.
2. Backes D, Rinkel GJ, Kemperman H, Linn FH, Vergouwen MD. Time-dependent test characteristics of head computed tomography in patients suspected of nontraumatic subarachnoid hemorrhage. Stroke. 2012;43:2115-2119.
3. Perry JJ, Stiell IG, Sivilotti ML, Bullard MJ, Emond M, Symington C et al. Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study. BMJ. 2011;343:d4277.
Berkhemer OA, Jansen IGH, Beumer D, Fransen PSS, van den Berg LA, Yoo AJ, et al. Collateral Status on Baseline Computed Tomographic Angiography and Intra-Arterial Treatment Effect in Patients With Proximal Anterior Circulation Stroke. Stroke. 2016
In this post-hoc analysis of the MR CLEAN study, collaterals were graded on baseline CTA using a 4-point scale where 0 was absent, 1 for poor (>0% and ≤50% filling of the occluded territory), 2 for moderate (> 50% and < 100% filling of the occluded territory), and 3 for good collaterals (100% filling of the occluded territory). There was an independent and significant modification of the treatment effect on the primary outcome of shift in direction of better outcome on the mRS. In addition, there was a shift in the distribution on the mRS in favor of intervention across all collateral grades except those with grade 0; the strongest shift was in patients with grade 3 collaterals. Patients with grade 3 collaterals had a 29.5% absolute increase in the chance of becoming functionally independent at day 90 (mRS 0-2), whereas in patients with grade 0 collaterals, none of the patients achieved functional independence at day 90.
Citing the high prevalence of cognitive impairment in patients with stroke, the authors call for better methods to easily detect cognitive impairment in this population. The authors aim to validate the Montreal Cognitive Assessment (MoCA) for classifying patients into three groups: low-, intermediate- and high-likelihood of moderate-severe cognitive impairment.
Three hundred and ninety patients referred to a stroke prevention clinic after stroke or TIA or other potentially cerebrovascular disease completed the MoCA. The mean age was 62 (range 17-94), and 53% were female. Patients were non-aphasic and English-speaking. Of the 390 patients, 34% had ischemic or hemorrhagic stroke, 34% had possible or probable TIA, and 32% had other vascular or non-vascular diagnoses (e.g. migraine). The gold standard for receiver operator characteristic/area under the curve analyses was an extensive neuropsychological battery.
The median MoCA score was 25 and did not differ significantly between diagnosis groups. By neuropsychological testing, 13% had moderate-severe cognitive impairment, and 30% had mild impairment.
Using a single cut-point for classification as moderate-severe impairment, test characteristics were optimal for MoCA <23 (sensitivity 60%, specificity 90%).
When two cut-points were assessed, the intermediate likelihood range was 23-27. In other words, a score of >27 reliably excluded patients with moderate-severe impairment (sensitivity 96%, negative predictive value 98%). A score of <23 reliably identified patients with moderate-severe impairment (specificity 90%, positive predictive value 49%). Of patients scoring in the intermediate likelihood range (23-27), 8% had moderate-severe impairment. The authors do not report the breakdown of the remaining 92% in terms of mild versus no cognitive impairment.
Jay Shah, MD
Saxena A, Anderson CS, Wang X, Sato S, Arima H, Chan E, et al. Prognostic Significance of Hyperglycemia in Acute Intracerebral Hemorrhage: The INTERACT2 Study. Stroke. 2016
Known prognostic factors of intracerebral hemorrhage (ICH) are hematoma volume and clinical severity. Hyperglycemia is associated with adverse outcomes in various medical conditions but its impact on ICH is relatively unknown. In this study, the authors seek to quantify risk associations of hyperglycemia and diabetes in patients that participated in the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). This study evaluated intense versus standard blood pressure control in ICH patients. Blood glucose level and history of diabetes was recorded at enrollment. Primary outcome was death or major disability. Secondary outcomes included serious adverse events such as neurological deterioration.
1348 (51%) patients had hyperglycemia and 292 (11%) had diabetes. After adjusting for confounding factors, hyperglycemic patients were significantly more often female, had greater cortical hematomas, higher systolic blood pressure and larger hematomas with intraventricular extension. There was a continuous relationship between baseline glucose level and death or disability (OR 1.29). Hyperglycemic patients had significantly greater frequency of early neurologic deterioration but there was no difference in hematoma expansion.
This study shows that elevated glucose levels and diabetes are associated with worse outcomes. An interesting element to these results indicate that the adverse outcomes are specific to the effects of hyperglycemia rather than simply a history of diabetes which impacted outcomes by increased cardiovascular event risk. While hyperglycemia and diabetes are certainly related, this suggests that adequate control of diabetes, and this lower blood glucose levels, may negate the potential risk of adverse outcomes following ICH. However, it is important to realize that INTERACT2 was not powered to evaluate hyperglycemia and therefore a causal relationship between hyperglycemia and outcomes cannot necessarily be established. Nonetheless, the study does elucidate a potential relationship and determining the pathophysiological mechanism remains an important biological query. Animal studies suggest that hyperglycemia plays a role in free radical generation which in turn disrupts blood-brain barrier and enhances edema. A possible limitation of this study is that hyperglycemia is based on a single time point and future studies should address effect of persistent hyperglycemia on outcomes. Ultimately, a trial designed to specifically control hyperglycemia should elucidate further this relationship and whether intervention improves outcomes.
Luciana Catanese, MD
Overall, results of this trial are consistent with prior data that shows that previously dependent patients are sicker at baseline with more comorbidities and prescribed medications, tend to score higher on the NIHSS due to the accumulation of deficits and have a higher overall mortality. However, whether or not dependent patients still benefit from IVT remains unanswered and more research looking into this topic is warranted. In the meantime, IVT should continue to be offered to previously dependent AIS patients.