Timothy J. Kleinig

A multicentre, randomized, double-blinded, placebo-controlled phase III study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND)

Background and hypothesis Thrombolytic therapy with tissue plasminogen activator is effective for acute ischaemic stroke within 4·5 h of onset. Patients who wake up with stroke are generally ineligible for stroke thrombolysis. We hypothesized that ischaemic stroke patients with significant penumbral mismatch on either magnetic resonance imaging or computer tomography at three- (or 4·5 depending on local guidelines) to nine-hours from stroke onset, or patients with wake-up stroke within nine-hours from midpoint of sleep duration, would have improved clinical outcomes when given tissue plasminogen activator compared to placebo. Study design EXtending the time for Thrombolysis in Emergency Neurological Deficits is an investigator-driven, Phase III, randomized, multicentre, double-blind, placebo-controlled study. Ischaemic stroke patients presenting after the three- or 4·5-h treatment window for tissue plasminogen activator and within nine-hours of stroke onset or with wake-up stroke within nine-hours from the midpoint of sleep duration, who fulfil clinical (National Institutes of Health Stroke Score ≥4–26 and prestroke modified Rankin Scale <2) will undergo magnetic resonance imaging or computer tomography. Patients who also meet imaging criteria (infarct core volume <70 ml, perfusion lesion : infarct core mismatch ratio >1·2, and absolute mismatch >10 ml) will be randomized to either tissue plasminogen activator or placebo. Study outcome The primary outcome measure will be modified Rankin Scale 0–1 at day 90. Clinical secondary outcomes include categorical shift in modified Rankin Scale at 90 days, reduction in the National Institutes of Health Stroke Score by 8 or more points or reaching 0–1 at day 90, recurrent stroke, or death. Imaging secondary outcomes will include symptomatic intracranial haemorrhage, reperfusion and or recanalization at 24 h and infarct growth at day 90.

The distinctive movement disorder of ovarian teratoma-associated encephalitis

The movement disorder observed in four cases of ovarian teratoma associated encephalitis is described. The illness began with neuropsychiatric symptoms and was followed by prolonged unresponsiveness, respiratory failure, and autonomic instability. The movement disorder consisted of semirhythmic repetitive bulbar and limb movements and persisted during prolonged periods of unresponsiveness, diminishing as awareness returned. The characteristics of the movement disorder differed from recognized dyskinesias. It is suggested that interruption of forebrain corticostriatal inputs by anti‐N‐methyl‐D‐aspartate (NMDA) receptor antibodies removes tonic inhibition of brainstem pattern generators releasing primitive patterns of bulbar and limb movement. Recognition of the distinctive movements should prompt a search for an ovarian teratoma since the condition is responsive to tumor resection and immunomodulation.

A multicenter, randomized, controlled study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits with Intra-Arterial therapy (EXTEND-IA)

Background and Hypothesis Thrombolysis with tissue plasminogen activator is proven to reduce disability when given within 4.5 h of ischemic stroke onset. However, tissue plasminogen activator only succeeds in recanalizing large vessel arterial occlusion in a minority of patients. We hypothesized that anterior circulation ischemic stroke patients, selected with ‘dual target’ vessel occlusion and evidence of salvageable brain using computed tomography or magnetic resonance imaging ‘mismatch’ within 4.5 h of onset, would have improved reperfusion and early neurological improvement when treated with intra-arterial clot retrieval after intravenous tissue plasminogen activator compared with intravenous tissue plasminogen activator alone. Study Design EXTEND-IA is an investigator-initiated, phase II, multicenter prospective, randomized, open-label, blinded-endpoint study. Ischemic stroke patients receiving standard 0.9 mg/kg intravenous tissue plasminogen activator within 4.5 h of stroke onset who have good prestroke functional status (modified Rankin Scale <2, no upper age limit) will undergo multimodal computed tomography or magnetic resonance imaging. Patients who also meet dual target imaging criteria: vessel occlusion (internal carotid or middle cerebral artery) and mismatch (perfusion lesion: ischemic core mismatch ratio >1.2, absolute mismatch >10 ml, ischemic core volume <70 ml) will be randomized to either clot retrieval with the Solitaire FR device after full dose intravenous tissue plasminogen activator, or tissue plasminogen activator alone. Study Outcomes The coprimary outcome measure will be reperfusion at 24 h and favorable clinical response (reduction in National Institutes of Health Stroke Scale by ≥8 points or reaching 0–1) at day 3. Secondary outcomes include modified Rankin Scale at day 90, death, and symptomatic intracranial hemorrhage.

Adelaide Stroke Incidence Study Declining Stroke Rates but Many Preventable Cardioembolic Strokes

Background and Purpose— Stroke incidence rates are in flux worldwide because of evolving risk factor prevalence, risk factor control, and population aging. Adelaide Stroke Incidence Study was performed to determine the incidence of strokes and stroke subtypes in a relatively elderly population of 148 000 people in the Western suburbs of Adelaide. Methods— All suspected strokes were identified and assessed in a 12-month period from 2009 to 2010. Standard definitions for stroke and stroke fatality were used. Ischemic stroke pathogenesis was classified by the Trial of ORG 10172 in Acute Stroke Treatment criteria. Results— There were 318 stroke events recorded in 301 individuals; 238 (75%) were first-in-lifetime events. Crude incidence rates for first-ever strokes were 161 per 100 000 per year overall (95% confidence interval [CI], 141–183), 176 for men (95% CI, 147–201), and 146 for women (95% CI, 120–176). Adjusted to the world population rates were 76 overall (95% CI, 59–94), 91 for men (95% CI, 73–112), and 61 for women (95% CI, 47–78). The 28-day case fatality rate for first-ever stroke was 19% (95% CI, 14–24); the majority were ischemic (84% [95% CI, 78–88]). Intracerebral hemorrhage comprised 11% (8–16), subarachnoid hemorrhage 3% (1–6), and 3% (1–6) were undetermined. Of the 258 ischemic strokes, 42% (95% CI, 36–49) were of cardioembolic pathogenesis. Atrial fibrillation accounted for 36% of all ischemic strokes, of which 85% were inadequately anticoagulated. Conclusions— Stroke incidence in Adelaide has not increased compared with previous Australian studies, despite the aging population. Cardioembolic strokes are becoming a higher proportion of all ischemic strokes.

The Spot Sign and Tranexamic Acid on Preventing ICH Growth – AUStralasia Trial (STOP-AUST): Protocol of a Phase II Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial

Rationale No evidence-based acute therapies exist for intracerebral hemorrhage. Intracerebral hemorrhage growth is an important determinant of patient outcome. Tranexamic acid is known to reduce hemorrhage in other conditions. Aim The study aims to test the hypothesis that intracerebral hemorrhage patients selected with computed tomography angiography contrast extravasation ‘spot sign’ will have lower rates of hematoma growth when treated with intravenous tranexamic acid within 4·5-hours of stroke onset compared with placebo. Design The Spot sign and Tranexamic acid On Preventing ICH growth – AUStralasia Trial is a multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled, investigator-initiated, academic Phase II trial. Intracerebral hemorrhage patients fulfilling clinical criteria (e.g. Glasgow Coma Scale >7, intracerebral hemorrhage volume <70 ml, no identified secondary cause of intracerebral hemorrhage, no thrombotic events within the previous 12 months, no planned surgery) and demonstrating contrast extravasation on computed tomography angiography will receive either intravenous tranexamic acid 1 g 10-min bolus followed by 1 g eight-hour infusion or placebo. A second computed tomography will be performed at 24 ± 3 hours to evaluate intracerebral hemorrhage growth and patients followed up for three-months. Study outcomes The primary outcome measure is presence of intracerebral hemorrhage growth by 24 ± 3 hours, defined as either >33% or >6 ml increase from baseline, and will be adjusted for baseline intracerebral hemorrhage volume. Secondary outcome measures include growth as a continuous measure, thromboembolic events, and the three-month modified Rankin Scale score. Discussion This is the first trial to evaluate the efficacy of tranexamic acid in intracerebral hemorrhage patients selected based on an imaging biomarker of high likelihood of hematoma growth. The trial is registered as NCT01702636.

Why Calls for More Routine Carotid Stenting Are Currently Inappropriate: An International, Multispecialty, Expert Review and Position Statement

Why Calls for More Routine Carotid Stenting Are Currently Inappropriate An International, Multispecialty, Expert Review and Position Statement

Automatic nonsubjective estimation of antigen content visualized by immunohistochemistry using color deconvolution.

We describe a method for the automatic, nonsubjective estimation of 3,3′ diaminobenzidine (DAB) in digital images obtained from routine central nervous system immunohistochemistry using freely available, platform-independent public domain image processing software. This technique estimates the amount of antigen visualized but does not measure antigen content directly. Combined with whole brain section high-resolution scanning, a “virtual dissection” (extracting the region of interest) makes it possible to estimate relative antigen content in either subcellular structures, specific brain regions, or in whole tissue sections at magnifications up to 40×. The digital image is processed using Ruifrok and Johnstons color deconvolution method to separate the brown DAB chromogen from the hematoxylin counterstain on a microscope slide. A monochrome image representing the DAB content is then subjected to frequency analysis using NIH-ImageJ and a weighting calculation to estimate the amount of DAB (antigen) as a dimensionless index. The method described produces results that agree with enzyme-linked immunosorbent assays, and is automatic and nonsubjective. The method could easily be adapted to other types of tissue or cell cultures.

Clinical Associations and Causes of Convexity Subarachnoid Hemorrhage

Background and Purpose— It has been previously found noted that ≈15% to 20% of subarachnoid hemorrhage (SAH) is nonaneurysmal. Nontraumatic convexity SAH (cSAH) is increasingly recognized. Data concerning incidence and associations are scant. Methods— We identified all SAH-coded cases from South Australian public hospitals between January 2005 and July 2011. Electronic discharge summaries were reviewed, and cases of cSAH were ascertained. Clinical and radiological features were recorded, and pathogenesis was assigned. Results— Of 742 cases with SAH, 41 (6%) cases were cSAH, giving a minimum population annual incidence of 5.1 per million (95% confidence interval, 3.7–7.0). Median age was 70 years (interquartile range, 48–79). Commonest causes were cerebral amyloid angiopathy (39%), reversible cerebral vasoconstriction syndrome (17%), cerebral venous sinus thrombosis (10%), large-vessel stenotic atherosclerosis (10%), and posterior reversible encephalopathy syndrome (5%). No cause was identified in 20% (mostly elderly patients with incomplete evaluation). Most (63%) presented with transient neurological symptoms. Many (49%) were misdiagnosed as transient ischemic attacks and treated inappropriately with antithrombotics. Conclusions— cSAH comprises a significant proportion of SAH. Commonest causes are cerebral amyloid angiopathy in the elderly and reversible cerebral vasoconstriction syndrome in the young, but differential diagnosis is broad. Misdiagnosis is common and leads to potentially harmful treatments.

Ischaemic stroke among young people aged 15 to 50 years in Adelaide, South Australia.

Objectives: To report risk factors, aetiology and neuroimaging features among a large series of young Australian patients who were admitted to hospital for a first‐ever occurrence of ischaemic stroke; to analyse the effect of age, sex and ethnicity on the presence of risk factors; and to compare Australian and overseas data.

Convexity subarachnoid haemorrhage associated with bilateral internal carotid artery stenoses

JO N 3106 Mild right-sided weakness and sensory disturbance was found on examination. Bilateral carotid bruits were noted. Computerised tomography (CT) demonstrated left inferior temporal convexity SAH (Fig. 1 A), confirmed on MRI (Fig. 1 B). Left middle cerebral artery (MCA) territory restricted diffusion foci were also noted (Fig. 1 C). Angiography demonstrated bilateral tight atherosclerotic internal carotid artery (ICA) stenoses (Fig. 1 D) and significant posterior-anterior pial collaterals. Sequential endarterectomies confirmed atherosclerosis. Timothy John Kleinig Thomas Edward Kimber Philip Douglas Thompson