A Pragmatic Randomized Trial Comparing Surgical Clipping and Endovascular Treatment of Unruptured Intracranial Aneurysms.

BACKGROUND AND PURPOSE: Surgical clipping and endovascular treatment are commonly used in patients with unruptured intracranial aneurysms. We compared the safety and efficacy of the 2 treatments in a randomized trial. MATERIALS AND METHODS: Clipping or endovascular treatments were randomly allocated to patients with one or more 3- to 25-mm unruptured intracranial aneurysms judged treatable both ways by participating physicians. The study hypothesized that clipping would decrease the incidence of treatment failure from 13% to 4%, a composite primary outcome defined as failure of aneurysm occlusion, intracranial hemorrhage during follow-up, or residual aneurysms at 1 year, as adjudicated by a core lab. Safety outcomes included new neurologic deficits following treatment, hospitalization of >5 days, and overall morbidity and mortality (mRS > 2) at 1 year. There was no blinding. RESULTS: Two hundred ninety-one patients were enrolled from 2010 to 2020 in 7 centers. The 1-year primary outcome, ascertainable in 290/291 (99%) patients, was reached in 13/142 (9%; 95% CI, 5%-15%) patients allocated to surgery and in 28/148 (19%; 95% CI, 13%-26%) patients allocated to endovascular treatments (relative risk: 2.07; 95% CI, 1.12-3.83; P = .021). Morbidity and mortality (mRS >2) at 1 year occurred in 3/143 and 3/148 (2%; 95% CI, 1%-6%) patients allocated to surgery and endovascular treatments, respectively. Neurologic deficits (32/143, 22%; 95% CI, 16%-30% versus 19/148, 12%; 95% CI, 8%-19%; relative risk: 1.74; 95% CI, 1.04-2.92; P = .04) and hospitalizations beyond 5 days (69/143, 48%; 95% CI, 40%-56% versus 12/148, 8%; 95% CI, 5%-14%; relative risk: 0.18; 95% CI, 0.11-0.31; P < .001) were more frequent after surgery. CONCLUSIONS: Surgical clipping is more effective than endovascular treatment of unruptured intracranial aneurysms in terms of the frequency of the primary outcome of treatment failure. Results were mainly driven by angiographic results at 1 year.

Two cases of non-parasitic splenic cysts and spleen-preserving therapy.

We review two different presentations of non-parasitic splenic cysts, both of which are post-traumatic in aetiology. The first case was of slower onset and was managed electively. The second case was of acute onset and was managed as an emergency. Non-parasitic splenic cysts are uncommon and the optimal management strategy for them is not well defined. Historically, treatment has been with open splenectomy; however, infection rates following this surgery have been high, making it an unattractive management option. Both cases were managed successfully with laparoscopic fenestration with no recurrence at subsequent follow-up.

Multimodal CT in Acute Stroke.

PURPOSE OF REVIEW: Multimodal CT imaging (non-contrast CT, NCCT; CT angiography, CTA; and CT Perfusion, CTP) is central to acute ischemic stroke diagnosis and treatment. We reviewed the purpose and interpretation of each component of multimodal CT, as well as the evidence for use in routine care. RECENT FINDINGS: Acute stroke thrombolysis can be administered immediately following NCCT in acute ischemic stroke patients assessed within 4.5 h of symptom onset. Definitive identification of a large vessel occlusion (LVO) requires vascular imaging, which is easily achieved with CTA. This is critical, as the standard of care for LVO within 6 h of onset is now endovascular thrombectomy (EVT). CTA source images can also be used to estimate the efficacy of collateral flow in LVO patients. The final component (CTP) permits a more accurate assessment of the extent of the ischemic penumbra. Complete multimodal CT, including objective penumbral measurement with CTP, has been used to extend the EVT window to 24 h. There is also randomized controlled trial evidence for extension of the IV thrombolysis window to 9 h with multimodal CT. Although there have been attempts to assess for responders to reperfusion strategies beyond 6 h ("late window") using collateral grades, the only evidence for treatment of this group of patients is based on selection using multimodal CT including CTP. The development of fully automated software providing quantitative ischemic penumbral and core volumes has facilitated the adoption of CTP and complete multimodal CT into routine clinical use. Multimodal CT is a powerful imaging algorithm that is central to current ischemic stroke patient care.

Canadian Stroke Best Practice Recommendations for Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care, 6th Edition, Update 2018.

The 2018 update of the Canadian Stroke Best Practice Recommendations for Acute Stroke Management, 6th edition, is a comprehensive summary of current evidence-based recommendations, appropriate for use by healthcare providers and system planners caring for persons with very recent symptoms of acute stroke or transient ischemic attack. The recommendations are intended for use by a interdisciplinary team of clinicians across a wide range of settings and highlight key elements involved in prehospital and Emergency Department care, acute treatments for ischemic stroke, and acute inpatient care. The most notable changes included in this 6th edition are the renaming of the module and its integration of the formerly separate modules on prehospital and emergency care and acute inpatient stroke care. The new module, Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care is now a single, comprehensive module addressing the most important aspects of acute stroke care delivery. Other notable changes include the removal of two sections related to the emergency management of intracerebral hemorrhage and subarachnoid hemorrhage. These topics are covered in a new, dedicated module, to be released later this year. The most significant recommendation updates are for neuroimaging; the extension of the time window for endovascular thrombectomy treatment out to 24 h; considerations for treating a highly selected group of people with stroke of unknown time of onset; and recommendations for dual antiplatelet therapy for a limited duration after acute minor ischemic stroke and transient ischemic attack. This module also emphasizes the need for increased public and healthcare provider's recognition of the signs of stroke and immediate actions to take; the important expanding role of paramedics and all emergency medical services personnel; arriving at a stroke-enabled Emergency Department without delay; and launching local healthcare institution code stroke protocols. Revisions have also been made to the recommendations for the triage and assessment of risk of recurrent stroke after transient ischemic attack/minor stroke and suggested urgency levels for investigations and initiation of management strategies. The goal of this updated guideline is to optimize stroke care across Canada, by reducing practice variations and reducing the gap between current knowledge and clinical practice.

Thrombolysis and thrombectomy in patients treated with dabigatran with acute ischemic stroke: Expert opinion.

Systemic thrombolysis with rt-PA is contraindicated in patients with acute ischemic stroke anticoagulated with dabigatran. This expert opinion provides guidance on the use of the specific reversal agent idarucizumab followed by rt-PA and/or thrombectomy in patients with ischemic stroke pre-treated with dabigatran. The use of idarucizumab followed by rt-PA is covered by the label of both drugs.

Cerebral Perfusion Pressure is Maintained in Acute Intracerebral Hemorrhage: A CT Perfusion Study.

BACKGROUND AND PURPOSE: Although blood pressure reduction has been postulated to result in a fall in cerebral perfusion pressure in patients with intracerebral hemorrhage, the latter is rarely measured. We assessed regional cerebral perfusion pressure in patients with intracerebral hemorrhage by using CT perfusion source data. MATERIALS AND METHODS: Patients with acute primary intracerebral hemorrhage were randomized to target systolic blood pressures of <150 mm Hg (n = 37) or <180 mm Hg (n = 36). Regional maps of cerebral blood flow, cerebral perfusion pressure, and cerebrovascular resistance were generated by using CT perfusion source data, obtained 2 hours after randomization. RESULTS: Perihematoma cerebral blood flow (38.7 ± 11.9 mL/100 g/min) was reduced relative to contralateral regions (44.1 ± 11.1 mL/100 g/min, P = .001), but cerebral perfusion pressure was not (14.4 ± 4.6 minutes(-1) versus 14.3 ± 4.8 minutes(-1), P = .93). Perihematoma cerebrovascular resistance (0.34 ± 0.11 g/mL) was higher than that in the contralateral region (0.30 ± 0.10 g/mL, P < .001). Ipsilateral and contralateral cerebral perfusion pressure in the external (15.0 ± 4.6 versus 15.6 ± 5.3 minutes(-1), P = .15) and internal (15.0 ± 4.8 versus 15.0 ± 4.8 minutes(-1), P = .90) borderzone regions were all similar. Borderzone cerebral perfusion pressure was similar to mean global cerebral perfusion pressure (14.7 ± 4.7 minutes(-1), P ≥ .29). Perihematoma cerebral perfusion pressure did not differ between blood pressure treatment groups (13.9 ± 5.5 minutes(-1) versus 14.8 ± 3.4 minutes(-1), P = .38) or vary with mean arterial pressure (r = -0.08, [-0.10, 0.05]). CONCLUSIONS: Perihematoma cerebral perfusion pressure is maintained despite increased cerebrovascular resistance and reduced cerebral blood flow. Aggressive antihypertensive therapy does not affect perihematoma or borderzone cerebral perfusion pressure. Maintenance of cerebral perfusion pressure provides physiologic support for the safety of blood pressure reduction in intracerebral hemorrhage.

Challenges and misconceptions in the aetiology and management of atrial fibrillation-related strokes.

Strokes, whether ischaemic or haemorrhagic, are the most feared complications of atrial fibrillation (AF) and its treatment. Vitamin K antagonists have been the mainstay of stroke prevention. Recently, direct oral anticoagulants have been introduced. The advantages and disadvantages of these treatment strategies have been extensively discussed. In this narrative review, we discuss dilemmas faced by primary care clinicians in the context of stroke and transient ischaemic attack (TIA) in patients with AF. We discuss the classification of stroke, the different types of stroke seen with AF, the prognosis of AF-related strokes, the early management after AF-related stroke or TIA and the therapeutic options after anticoagulant-associated intracerebral haemorrhage. Most importantly, we aim to dispel common misconceptions on the part of non-stroke specialists that can lead to suboptimal stroke prevention and management.

Innovation in e-learning: learning for all.

Online learning is not a new concept for most in the medical profession. However, surgical oncology is poorly represented, and in a world of ever-changing research evidence, relying on published texts may not be efficient learning or an accurate representation of current practice for many trainees. This article demonstrates how our educational collaborative, ePOSSOM, approaches the problem. It outlines the development process of the whole project between ecancer and the Severn School of Surgery, UK, and provides links to the pilot completed modules on pancreatic cancer and its treatment for the reader to experience.

DWI reversal is associated with small infarct volume in patients with TIA and minor stroke.

BACKGROUND AND PURPOSE: More than half of patients with TIA/minor stroke have ischemic lesions on early DWI, which represent irreversibly damaged tissue. The presence and volume of DWI lesions predict early deterioration in this population. We aimed to study the rate and implications of DWI reversal in patients with TIA/minor stroke. MATERIALS AND METHODS: Patients with TIA/minor stroke were prospectively enrolled and imaged within 24 hours of onset. Patients were followed for 3 months with repeat MR imaging either at day 30 or 90. Baseline DWI/PWI and follow-up FLAIR final infarct volumes were measured. RESULTS: Of 418 patients included, 55.5% had DWI and 37% had PWI (time-to-peak of the impulse response ≥2 seconds' delay) lesions at baseline. The median time from symptom onset to baseline and follow-up imaging was 13.4 (interquartile range, 12.7) and 78.73 hours (interquartile range, 60.2), respectively. DWI reversal occurred in 5.7% of patients. The median DWI lesion volume was significantly smaller in those with reversal (0.26 mL, interquartile range = 0.58 mL) compared with those without (1.29 mL, interquartile range = 3.6 mL, P = .002); 72.7% of DWI reversal occurred in cortically based lesions. Concurrent tissue hypoperfusion (time-to-peak of the impulse response ≥2 seconds) was seen in 36.4% of those with DWI reversal versus 62.4% without (P = .08). DWI reversal occurred in 3.3% of patients with penumbral patterns (time-to-peak of the impulse response ≥6 seconds - DWI) > 0 and in 6.8% of those without penumbral patterns (P = .3). The severity of hypoperfusion, defined as greater prolongation of time-to-peak of the impulse response (≥2, ≥4, ≥6, ≥8 seconds), did not affect the likelihood of DWI reversal (linear trend, P = .147). No patient with DWI reversal had an mRS score of ≥2 at 90 days versus 18.2% of those without reversal (P = .02). CONCLUSIONS: DWI reversal is uncommon in patients with TIA/minor stroke and is more likely to occur in those with smaller baseline lesions. DWI reversal should not have a significant effect on the accuracy of penumbra definition.

Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.

BACKGROUND: Early administration of intravenous recombinant tissue plasminogen activator (rt-PA) after ischaemic stroke improves outcome. Previous analysis of combined data from individual patients suggested potential benefit beyond 3 h from stroke onset. We re-examined the effect of time to treatment with intravenous rt-PA (alteplase) on therapeutic benefit and clinical risk by adding recent trial data to the analysis. METHODS: We added data from ECASS III (821 patients) and EPITHET (100 patients) to a pool of common data elements from six other trials of alteplase for acute stroke (2775 patients). We used multivariate logistic regression to assess the relation of stroke onset to start of treatment (OTT) with treatment on favourable 3-month outcome (defined as modified Rankin score 0-1), mortality, and occurrence and outcome of clinically relevant parenchymal haemorrhage. The presence of an arterial occlusion was inferred from the patient's symptoms and absence of haemorrhage or other causes of ischaemic stroke. Vascular imaging was not a requirement in the trials. All patients with confirmed OTT within 360 min were included in the analysis. FINDINGS: Treatment was started within 360 min of stroke onset in 3670 patients randomly allocated to alteplase (n=1850) or to placebo (n=1820). Odds of a favourable 3-month outcome increased as OTT decreased (p=0.0269) and no benefit of alteplase treatment was seen after around 270 min. Adjusted odds of a favourable 3-month outcome were 2.55 (95% CI 1.44-4.52) for 0-90 min, 1.64 (1.12-2.40) for 91-180 min, 1.34 (1.06-1.68) for 181-270 min, and 1.22 (0.92-1.61) for 271-360 min in favour of the alteplase group. Large parenchymal haemorrhage was seen in 96 (5.2%) of 1850 patients assigned to alteplase and 18 (1.0%) of 1820 controls, with no clear relation to OTT (p=0.4140). Adjusted odds of mortality increased with OTT (p=0.0444) and were 0.78 (0.41-1.48) for 0-90 min, 1.13 (0.70-1.82) for 91-180 min, 1.22 (0.87-1.71) for 181-270 min, and 1.49 (1.00-2.21) for 271-360 min. INTERPRETATION: Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous alteplase when treated up to 4.5 h. To increase benefit to a maximum, every effort should be taken to shorten delay in initiation of treatment. Beyond 4.5 h, risk might outweigh benefit. FUNDING: None.

Acute stroke imaging. Part I: Fundamentals.

Neuroimaging is essential to stroke diagnosis and management. To date, the non-contrast CT has served as our main diagnostic tool. Although brain parenchymal changes visible on CT do provide valuable prognostic information, they provide limited insight into the potential for tissue salvage in response to reperfusion therapy, such as thrombolysis. Newer advanced CT and MRI based imaging techniques have increased the detection sensitivity for hyperacute and chronic parenchymal changes, including ischemia and hemorrhage, permit visualization of blood vessels and cerebral blood flow. This review outlines the basic principles underlying acquisition and interpretation of these newer imaging modalities in the setting of acute stroke. The utility of advanced brain parenchymal and blood flow imaging in the context of acute stroke patient management is also discussed. Part II in this series is a discussion of how these techniques can be used to rationally select appropriate patients for thrombolysis based on pathophysiological data.

Acute stroke imaging. Part II: The ischemic penumbra.

In acute ischemic stroke, the volume of threatened but potentially salvageable tissue, i.e. the ischemic penumbra, is critical to the success of all acute therapeutic interventions, most notably thrombolysis. Despite the availability of both CT and MRI based techniques to detect and assess the penumbra, advanced imaging of this type remains under-utilized. Although the optimal selection criteria are still being refined and technical improvements are ongoing, rapid imaging of the penumbra appears to be the most promising approach to expanding the acute thrombolysis population, as well as tailoring treatment based on specific pathophysiological findings. This second article in a two-part series reviews current evidence for penumbral-based treatment selection and discusses the barriers to implementation of these advanced imaging techniques in acute stroke management protocols.

Baseline diabetic status and admission blood glucose were poor prognostic factors in the EPITHET trial.

BACKGROUND: Previous data have suggested that diabetes and hyperglycemia predict poor outcome following stroke. We studied the prognostic impact of diabetes and admission blood glucose in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). METHODS: EPITHET was a prospective randomized placebo-controlled trial of intravenous tissue plasminogen activator (tPA) in the 3- to 6-hour time window. A preexisting diagnosis of diabetes was noted and baseline serum glucose was measured. RESULTS: Intravenous tPA attenuated infarct growth in non-diabetics, but not in diabetics (p = 0.029). In the tPA treatment group, admission blood glucose was higher among patients with poor functional outcome (p = 0.002). CONCLUSIONS: Diabetes and hyperglycemia attenuate the effects of tPA on infarct evolution. Future thrombolytic trials should consider randomizing patients by subgroups based on diabetic status and serum glucose levels.

Reversible cerebral vasoconstriction syndrome.

Reversible cerebral vasoconstriction syndromes (RCVS) are a group of disorders that have in common an acute presentation with headache, reversible vasoconstriction of cerebral arteries, with or without neurological signs and symptoms. In contrast to primary central nervous system vasculitis, they have a relatively benign course. We describe here a patient who was diagnosed with RCVS.

Therapeutic management of acute intracerebral haemorrhage.

Intracerebral haemorrhage (ICH) is a stroke resulting from spontaneous rupture of an intracranial vessel and is associated with high early mortality and long-term morbidity rates. With the exception of dedicated stroke units or neurocritical care, no surgical or medical intervention has been proven to effectively improve outcome following ICH. Pharmacotherapeutic considerations include optimal blood pressure control and the choice of antihypertensive agents. Acute haematoma expansion represents the most obvious acute treatment target. The use of haemostatic agents may have a role in ICH management; although it appears improved patient selection may be required before the use of these agents can be demonstrated clinically. In patients with anticoagulant-associated ICH, a number of therapeutic agents may be used to urgently reverse the coagulopathy, although further clinical trials are required. Recurrent bleeding and future thrombo-embolic event rates in patients who require anticoagulation following ICH risks are difficult to determine accurately, although risk stratification data are emerging. This article reviews the pathophysiology, natural history and the evidence supporting present therapeutic management practices for ICH. The authors' practice based on best available evidence is provided.

Amelogenins in human developing and mature dental pulp.

Amelogenins are a group of heterogenous proteins first identified in developing tooth enamel and reported to be present in odontoblasts. The objective of this study was to elucidate the expression and function of amelogenins in the human dentin-pulp complex. Developing human tooth buds were immunostained for amelogenin, and mRNA was detected by in situ hybridization. The effects of recombinant amelogenins on pulp and papilla cell proliferation were measured by Brd U immunoassay, and differentiation was monitored by alkaline phosphatase expression. Amelogenin protein was found in the forming dentin matrix, and amelogenin mRNA was localized in the dentin, presumably in the odontoblast processes. Proliferation of papilla cells was enhanced by recombinant human amelogenin rH72 (LRAP+ exon 4), while pulp cells responded to both rH72 and rH58 (LRAP), with no effect by rH174. These studies suggest that odontoblasts actively synthesize and secrete amelogenin protein during human tooth development, and that low-molecular-weight amelogenins can enhance pulp cell proliferation.

Elevated hematocrit is associated with reduced reperfusion and tissue survival in acute stroke.

BACKGROUND: Elevated hematocrit (Hct) contributes to blood viscosity and has an adverse effect in acute stroke. The authors investigated the influence of Hct on tissue fate using serial MRI in acute stroke patients. METHODS: The effects of Hct on reperfusion, penumbral salvage, and infarct expansion in 64 patients presenting within 24 hours of stroke onset were measured. MRI was performed at baseline (< 24 hours), days 3 to 5, and 90 days from stroke onset. RESULTS: Median Hct was 42% with a bimodal distribution. There was a strong inverse relationship between Hct and reperfusion (Spearman rho = -0.74, p < 0.0001). The odds of major reperfusion (> 50% resolution of the baseline perfusion-weighted imaging deficit) were significantly lower with increasing Hct (odds ratio [OR] = 0.53; 95% CI = 0.97 to 1.00), independent of age, perfusion, and diffusion lesion volumes and recombinant tissue plasminogen activator (rtPA) administration. There was a trend toward reduced penumbral salvage at days 3 to 5 with increasing Hct (p = 0.06, 95% CI = -4.76 to 0.14). An increasing Hct was a significant predictor of infarct growth (OR = 1.26, 95% CI = 1.00 to 1.59), independent of baseline perfusion and diffusion volumes and glucose. The effect of Hct on reperfusion and infarct expansion was similar irrespective of rtPA administration (p = 0.31) and independent of smoking status. CONCLUSIONS: Higher hematocrit (Hct) values have a significant independent association with reduced reperfusion and greater infarct size after ischemic stroke. An elevated Hct may also be a potential physiologic determinant of reduced penumbral salvage.