Can We Miniaturize CT Technology for a Successful Mobile Stroke Unit Roll-Out?

Mortality from stroke remains high in Australia, especially for patients located outside the metropolitan cities. This is because they have limited access to specialized stroke facilities for optimal stroke treatment. Mobile stroke units have the capability to take CT scanners out to the patient however current CT commercial scanner designs are large and heavy. As such, this paper aims to design and develop a lightweight CT scanner for use in a mobile stroke unit (either road-based or air-based ambulance) to bring healthcare solution to patients in the rural and remote areas. We used the engineering design optimization approach to redesign and reduce the weight of the existing CT scanner with without compromised it structural performance. We managed to reduce the weight the CT scanner by three-fold while reducing design costs by allowing numerous simulations to be performed using computer software to achieve our design goals. The results are not only useful to optimize CT scanner structure to retrofit on a mobile stroke unit, but also bring the medical device solution to the market and support scalable solution to the larger community. Such an advance will allow for improved equity in healthcare whereby patients can be treated irrespective of location.

Ten years of cerebral venous thrombosis: male gender and myeloproliferative neoplasm is associated with thrombotic recurrence in unprovoked events.

Cerebral venous thrombosis (CVT) is a rare venous thrombotic event. We review our local experience in the management of CVT in comparison to other venous thromboembolism (VTE) with specific focus on risk factors for thrombotic recurrence. Retrospective evaluation of consecutive CVT presentations from January 2005 to June 2015, at two major tertiary hospitals in Northeast Melbourne, Australia. This population was compared to a separate audit of 1003 consecutive patients with DVT and PE. Fifty-two patients (30 female, 22 male) with a median age of 40 (18-83) years, presented with 53 episodes of CVT. Twenty-nine episodes (55 %) were associated with an underlying risk factor, with hormonal risk factors in females being most common. The median duration of anticoagulation was 6 months with 11 receiving life-long anticoagulation. Eighty-one percent had residual thrombosis on repeat imaging, which was not associated with recurrence at the same or distant site. Nine (17 %) had CVT-related haemorrhagic transformation with two resultant CVT-related deaths (RR 22.5; p = 0.04). All three VTE recurrences occured in males with unprovoked events (RR 18.2; p = 0.05) who were subsequently diagnosed with myeloproliferative neoplasm (MPN). Compared to the non-cancer VTE population, non-cancer CVT patients were younger, had similar rate of provoked events and VTE recurrence, although with significantly higher rate of MPN diagnosis (RR 9.30 (2.29-37.76); p = 0.002) CVT is a rare thrombotic disorder. All recurrences in this audit occurred in male patients with unprovoked events and subsequent diagnosis of MPN, suggesting further evaluation for MPN may be warranted in patients with unprovoked CVT.

ICARUSS, the Integrated Care for the Reduction of Secondary Stroke trial: rationale and design of a randomized controlled trial of a multimodal intervention to prevent recurrent stroke in patients with a recent cerebrovascular event, ACTRN = 12611000264987.

BACKGROUND: The majority of strokes, both ischaemic and haemorrhagic, are attributable to a relatively small number of risk factors which are readily manageable in primary care setting. Implementation of best-practice recommendations for risk factor management is calculated to reduce stroke recurrence by around 80%. However, risk factor management in stroke survivors has generally been poor at primary care level. A model of care that supports long-term effective risk factor management is needed. AIM: To determine whether the model of Integrated Care for the Reduction of Recurrent Stroke (ICARUSS) will, through promotion of implementation of best-practice recommendations for risk factor management reduce the combined incidence of stroke, myocardial infarction and vascular death in patients with recent stroke or transient ischaemic attack (TIA) of the brain or eye. DESIGN: A prospective, Australian, multicentre, randomized controlled trial. SETTING: Academic stroke units in Melbourne, Perth and the John Hunter Hospital, New South Wales. SUBJECTS: 1000 stroke survivors recruited as from March 2007 with a recent (<3 months) stroke (ischaemic or haemorrhagic) or a TIA (brain or eye). RANDOMIZATION: Randomization and data collection are performed by means of a central computer generated telephone system (IVRS). INTERVENTION: Exposure to the ICARUSS model of integrated care or usual care. PRIMARY OUTCOME: The composite of stroke, MI or death from any vascular cause, whichever occurs first. SECONDARY OUTCOMES: Risk factor management in the community, depression, quality of life, disability and dementia. STATISTICAL POWER: With 1000 patients followed up for a median of one-year, with a recurrence rate of 7-10% per year in patients exposed to usual care, the study will have at least 80% power to detect a significant reduction in primary end-points CONCLUSION: The ICARUSS study aims to recruit and follow up patients between 2007 and 2013 and demonstrate the effectiveness of exposure to the ICARUSS model in stroke survivors to reduce recurrent stroke or vascular events and promote the implementation of best practice risk factor management at primary care level.

Salvage of the PWI/DWI mismatch up to 48 h from stroke onset leads to favorable clinical outcome.

BACKGROUND AND PURPOSE: In acute ischemic stroke perfusion/diffusion-weighted image, mismatch using magnetic resonance imaging approximates the ischemic penumbra. For early time windows, mismatch salvage improves clinical outcomes, but uncertainty exists at later time epochs. We hypothesized that (a) mismatch may exist up to 48 h; (b) the proportion of mismatch salvage is time independent; and (c) when salvaged, it improves clinical outcomes. METHODS: Magnetic resonance imaging was performed within 48 h of ischemic stroke. Perfusion-weighted image was defined by relative Tmax two-second delay. Perfusion/diffusion-weighted image mismatch was the perfusion-weighted image not overlapped by the diffusion-weighted image when coregistered. Infarct volume and disability (modified Rankin Score) were assessed at three-months. Mismatch salvage was the region not overlapped by final infarction. Favorable outcome was defined as modified Rankin Score 0-1. RESULTS: Sixty-six patients were studied [mean age 69.9 years (standard deviation 13.1), initial median National Institute of Health Stroke Scale 9.0 (interquartile range 6.0, 18.3)]. There was no relationship between time of stroke onset and the proportion of mismatch salvaged (P = 0.73). Age (adjusted odds ratio = 0.92, 95% confidence interval 0.86-0.98, P = 0.01), initial National Institute of Health Stroke Scale (adjusted odds ratio = 0.80, 95% confidence interval 0.70-0.92, P < 0.01), mismatch volume (adjusted odds ratio = 0.98, 95% confidence interval 0.968-0.1, P = 0.05), and percentage of mismatch salvage (adjusted odds ratio = 1.04, 95% confidence interval 0.99-1.07, P = 0.05) were independently associated with favorable outcome. CONCLUSION: Using coregistered perfusion/diffusion-weighted image criteria, mismatch persists up to 48 h post stroke. For the whole group, the proportion of mismatch salvage remains independent of time and, although the effect is small, its salvage is independently associated with improved clinical outcomes at three-months. Larger sample sizes are needed to determine the time limit for mismatch salvage.

The ASCOD phenotyping of ischemic stroke (Updated ASCO Phenotyping).

ASCO phenotyping (A: atherosclerosis; S: small-vessel disease; C: cardiac pathology; O: other causes) assigns a degree of likelihood of causal relationship to every potential disease (1 for potentially causal, 2 for causality is uncertain, 3 for unlikely causal but the disease is present, 0 for absence of disease, and 9 for insufficient workup to rule out the disease) commonly encountered in ischemic stroke describing all underlying diseases in every patient. In this new evolution of ASCO called ASCOD, we have added a 'D' for dissection, recognizing that dissection is a very frequent disease in young stroke patients. We have also simplified the system by leaving out the 'levels of diagnostic evidence', which has been integrated into grades 9 and 0. Moreover, we have also changed the cutoff for significant carotid or intracranial stenosis from 70% to more commonly used 50% luminal stenosis, and added a cardiogenic stroke pattern using neuroimaging. ASCOD captures and weights the overlap between all underlying diseases present in ischemic stroke patients.

Does the cognitive measure Cog-4 show improvement among patients treated with thrombolysis after acute stroke?

BACKGROUND: Although the established measure of disability post stroke, the modified Rankin Scale emphasizes motor function and may underestimate the importance of cognitive impairment in more disabled patients. A subset of four items from the National Institutes of Health Stroke Scale has been proposed to assess cognitive function after stroke (Cog-4), and to correlate with modified Rankin Scale. Items correspond to orientation, executive function, language, and inattention. We investigated responsiveness of Cog-4 to treatment with thrombolysis and whether it offers information that supplements modified Rankin Scale. METHODS: We included 6268 patients from the Virtual International Stroke Trials Archive: 2734 received intravenous thrombolysis and 3534 were treated conservatively. We compared day 90 outcomes between treated and untreated groups, by modified Rankin Scale (illustrative) and by Cog-4 (primary measure) adjusting for age, baseline National Institutes of Health stroke scale, hemispheric lateralisation as well as baseline Cog-4 and baseline National Institutes of Health Stroke Scale excluding baseline Cog-4 separately. Analysis of Cog-4 was repeated within strata of 90 day modified Rankin Scale. Statistical analyses included proportional odds logistic regression and Cochran-Mantel-Haenszel test. RESULTS: Modified Rankin Scale showed a difference between treatment groups of expected magnitude (odds ratio 1·56; 95% confidence interval 1·43-1·72; P < 0·001). After adjustment for imbalance in baseline prognostic factors, the distribution of Cog-4 scores at 90 days was better in thrombolysed patients compared with nonthrombolysed patients (odds ratio 1·31; 95% confidence interval 1·18-1·47; P = 0·006). However, Cog-4 analysis stratified by 90-day modified Rankin Scale was neutral between treatment groups (OR 1·01; 95% CI 0·90-1·14), and Cog-4 was not responsive to treatment group even within modified Rankin Scale categories 4 and 5 despite substantial cognitive deficits in these patients. CONCLUSION: Although Cog-4 may be responsive to treatment effects, it does not provide additional information beyond modified Rankin Scale assessment.

Multidisciplinary approach to carotid stenting.

BACKGROUND: Stroke neurologists, vascular surgeons, interventional neuroradiologists and interventional cardiologists have embraced carotid angioplasty and stenting (CAS) because of potential advantages over carotid endarterectomy (CEA). At Austin Health, a multidisciplinary neuro-interventional group was formed to standardise indications and facilitate training. The aims of this study were to describe our organisational model and to determine whether 30-day complications and early outcomes were similar to those of major trials. METHODS: A clinical protocol was developed to ensure optimal management. CAS was performed on patients with high medical risk for CEA, with technically difficult anatomy for CEA, or who were randomised to CAS in a trial. RESULTS: From October 2003 to May 2008, 47 patients (34 male, mean age 71.5) underwent CAS of 50 carotid arteries. Forty-three cases had ipsilateral carotid territory symptoms within the previous 12 months. The main indications for CAS were high risk for CEA (n= 17) and randomised to CAS (n= 21). Interventionists were proctored in 27 cases. The procedural success rate was 94% with two cases abandoned because of anatomical problems and one because of on-table angina. Hypotension requiring vasopressor therapy occurred in 12 cases (24%). The duration of follow up was one to 44 months (mean 6.8 months). The 30-day rate of peri-procedural stroke or death was 6% and the one-year rate of peri-procedural stroke or death or subsequent ipsilateral stroke was 10.6%. Restenosis occurred in 13% (all asymptomatic). CONCLUSION: A multidisciplinary approach is a useful strategy for initiating and sustaining a CAS programme.

Ischemic diffusion lesion reversal is uncommon and rarely alters perfusion-diffusion mismatch.

OBJECTIVE: The use of diffusion-weighted imaging (DWI) to define irreversibly damaged infarct core is challenged by data suggesting potential partial reversal of DWI abnormalities. However, previous studies have not considered infarct involution. We investigated the prevalence of DWI lesion reversal in the EPITHET Trial. METHODS: EPITHET randomized patients 3-6 hours from onset of acute ischemic stroke to tissue plasminogen activator (tPA) or placebo. Pretreatment DWI and day 90 T2-weighted images were coregistered. Apparent reversal of the acute ischemic lesion was defined as DWI lesion not incorporated into the final infarct. Voxels of CSF at follow-up were subtracted from regions of apparent DWI lesion reversal to adjust for infarct atrophy. All cases were visually cross-checked to exclude volume loss and coregistration inaccuracies. RESULTS: In 60 patients, apparent reversal involved a median 46% of the baseline DWI lesion (median volume 4.9 mL, interquartile range 2.6-9.5 mL) and was associated with less severe baseline hypoperfusion (p < 0.001). Apparent reversal was increased by reperfusion, regardless of the severity of baseline hypoperfusion (p = 0.02). However, the median volume of apparent reversal was reduced by 45% when CSF voxels were subtracted (2.7 mL, interquartile range 1.6-6.2 mL, p < 0.001). Perfusion-diffusion mismatch classification only rarely altered after adjusting the baseline DWI volume for apparent reversal. Visual comparison of acute DWI to subacute DWI or day 90 T2 identified minor regions of true DWI lesion reversal in only 6 of 93 patients. CONCLUSIONS: True DWI lesion reversal is uncommon in ischemic stroke patients. The volume of apparent lesion reversal is small and would rarely affect treatment decisions based on perfusion-diffusion mismatch.

The Virtual International Stroke Trials Archive (VISTA): results and impact on future stroke trials and management of stroke patients.

BACKGROUND: The Virtual International Stroke Trials Archive was established to improve stroke care and trial design through the collation, categorization and potential access to data sets from clinical trials for the treatment of stroke. METHODS: Virtual International Stroke Trials Archive currently provides access to a combined data set of 29 anonymised acute stroke trials and one acute stroke registry with data on >27,500 patients aged between 18 and 103 (mean 71) years. RESULTS: Virtual International Stroke Trials Archive has facilitated research across a broad canvas. The prognosis was poor in patients with very high blood pressure at the time of admission or with a wide variability of systolic blood pressure during the acute phase. The late occurrence of hyperthermia following an ischaemic stroke worsens the prognosis. Stroke lateralisation is not an important predictor of cardiac adverse events or 90-day mortality. Haemorrhagic transformation is seen frequently in patients with cardio-embolic strokes and is associated with a poor prognosis when occurring after the acute phase. Virtual International Stroke Trials Archive has allowed various prognostic models for patients with ischaemic or haemorrhagic stroke to be established and validated. More direct outcomes such as lesion volume can be useful in phase II clinical trials for determining whether a phase III trial should be undertaken. New outcome measures such as 'home time' may also strengthen future trials. On a worldwide level, the prognosis of stroke patients differs considerably between various countries. CONCLUSION: Virtual International Stroke Trials Archive provides an excellent opportunity for analysis of natural history data and prognosis. It has the potential to influence clinical trial design and implementation through exploratory data analyses.

Where will the next generation of stroke treatments come from?

Remarkable progress has occurred over the last two decades in stroke interventions. Many have been developed on the basis of their efficacy in other disorders. This "inheritance" approach should continue, but two areas where completely novel therapeutic targets might emerge are the stimulation of neuroplasticity and unraveling the genetic code of stroke heterogeneity (Table 2). For the former, the next steps are to identify small-molecule, nontoxic compounds that most effectively enhance plasticity in animal models, and then subject them to clinical trial in humans. For the latter, more and larger-scale cooperative GWASs in carefully phenotyped stroke populations are required to better understand the polygenic nature of cerebrovascular disease. Then, the physiological relevance of genetic abnormalities can be determined in in vitro and in vivo systems before candidate compounds are developed.

11C-PIB binding is increased in patients with cerebral amyloid angiopathy-related hemorrhage.

BACKGROUND: The in vivo diagnosis of cerebral amyloid angiopathy (CAA) is inferred from clinical and structural imaging features. (11)C-Pittsburgh compound B (PIB) is a PET ligand that binds to beta-amyloid in extracellular plaques and vessel walls. We hypothesized that patients with a clinical diagnosis of CAA-related hemorrhage (CAAH) have increased (11)C-PIB uptake and that the pattern differs from Alzheimer disease (AD). METHODOLOGY: Patients with CAAH based on established clinical criteria were studied using (11)C-PIB PET and were compared with age-matched controls and patients with AD. Distribution volume ratio (DVR) parametric maps were created using the cerebellar cortex as a reference region. RESULTS: Twelve patients with CAAH of mean age 73.9 (range 58-93) years were compared with 22 normal controls and 13 patients with AD of mean age 71.8 (59-83) and 73.8 (56-90) years, respectively. CAAH PIB median DVR binding was higher in cortical regions (1.69, interquartile range 1.44-1.97) compared with controls (1.32, 1.21-1.44, p = 0.002) but lower than AD (2.04, 1.93-2.26, p = 0.004). The occipital-global uptake ratio was lower among patients with AD than among patients with CAAH (p = 0.008), and the frontal-global uptake ratio was higher (p = 0.012). CONCLUSION: (11)C-Pittsburgh compound B (PIB) binding is moderately increased in most patients with probable cerebral amyloid angiopathy (CAA)-related intracerebral hemorrhage. The distribution may differ from that seen in Alzheimer disease. (11)C-PIB PET may assist in the in vivo diagnosis of CAA and serve as a surrogate marker for future therapeutic studies.

Sex differences in presentation, severity, and management of stroke in a population-based study.

OBJECTIVES: Women may have poorer outcomes after stroke than men because of differences in their acute management. We examined sex differences in presentation, severity, in-hospital treatment, and early mortality in a cohort of first-ever-in-a-lifetime stroke patients. METHODS: Data were collected from May 1, 1996, to April 30, 1999, in the North East Melbourne Stroke Incidence Study. Stroke symptoms, prestroke medical history, in-hospital investigations, admission and discharge medications, initial stroke severity, and 28-day mortality were recorded. Multivariable regression was used to estimate sex differences in treatment, investigations, and 28-day mortality. RESULTS: A total of 1,316 patients were included. Women were older (mean age 76 +/- 0.6 vs 72 +/- 0.6, p < 0.01), had more severe strokes (median NIH Stroke Scale score 6 vs 5, p < 0.01), and more likely to experience loss of consciousness (31% vs 23%, p = 0.003) and incontinence (22% vs 11%, p = 0.01) than men. Women were less often on lipid-lowering therapy on admission. Echocardiography and carotid investigations were less frequently performed in women due to greater age and stroke severity. Women had greater 28-day mortality (32% vs 21%, p < 0.001) and stroke severity (44% vs 36%, p = 0.01) than men, but adjustment for age, comorbidities, and stroke severity (for mortality only) completely attenuated these associations. CONCLUSION: Sex differences seen in this study were mostly explained by women's older age, greater comorbidity, and stroke severity. The reasons for differences according to age may need further examination.

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.

Postoperative analgesia and respiratory events in patients with symptoms of obstructive sleep apnoea.

Symptoms of obstructive sleep apnoea are common in patients presenting for surgery and are associated with increased morbidity. Analgesia contributes significantly to postoperative respiratory depression and obstruction, so we compared standard morphine patient-controlled analgesia with an opioid-sparing protocol (tramadol patient-controlled analgesia, parecoxib and rescue-only morphine) in these patients. Sixty-two patients presenting for elective surgery with body mass index > or = 28 and signs or symptoms suggesting obstructive sleep apnoea were randomised to receive either the opioid or opioid-sparing postoperative analgesia protocol, with continuous respiratory monitoring for 12 hours on the first postoperative night. The number of respiratory events (apnoeas and hypopnoeas) and oxygen desaturations were compared. There was no difference between treatment groups in the number of obstructive apnoeas, hypopnoeas or central apnoeas. However, central apnoeas and a rate of respiratory events > 15 per hour were related to postoperative morphine dose (P = 0.005 and P = 0.002). In patients at risk of obstructed breathing, intention to treat with an opioid-sparing analgesia protocol did not decrease the rate of respiratory events, although the rate was still related to the total morphine dose.

Hypertension and TIA.

Transient ischemic attack is a medical emergency because early stroke risk after transient ischemic attack is high. Hypertension is the most important modifiable risk factor for stroke and transient ischemic attack. The aims of this review are to provide a summary of the current knowledge concerning the relationship between blood pressure and transient ischemic attack, as well as outline issues regarding diurnal variation and the potential of chronotherapy (timing medications to accord with diurnal patterns of blood pressure). There is a strong relationship between hypertension and the incidence of transient ischemic attack and the subsequent short-term risk for stroke. Ambulatory blood pressure monitoring is a reliable diagnostic and monitoring tool for hypertension and provides additional information about diurnal variation in blood pressure. Different diurnal blood pressure patterns may confer variable stroke risk. Patients with stroke commonly have abnormal diurnal blood pressure patterns and this may relate, in part, to autonomic nervous system dysfunction. However, blood pressure patterns have not been systematically studied in patients with transient ischemic attack. Blood pressure remains poorly controlled in a large proportion of patients after transient ischemic attack and under-treatment and poor adherence are important factors. Chronotherapy for blood pressure may result in more effective blood pressure control. More research is needed in this area. Hypertension is strongly associated with transient ischemic attack. Diurnal blood pressure patterns may influence subsequent stroke risk after transient ischemic attack and more evidence is needed to inform clinical practice to improve blood pressure management for transient ischemic attack patients.

Very early mobilisation and complications in the first 3 months after stroke: further results from phase II of A Very Early Rehabilitation Trial (AVERT).

BACKGROUND: Interventions that may reduce the number and severity of potentially harmful post-stroke complications are desirable. This study explored whether very early and frequent mobilisation (VEM) affected complication type (immobility/stroke related), number and severity. METHODS: Secondary analysis from phase II, randomised controlled trial. Patients admitted within 24 h of stroke, whose physiological parameters fell within set limits, were randomised to either VEM, commencing <24 h, or standard care. Complications to 3 months were recorded by a blinded assessor and classified by a neurologist. Analysis was intention to treat. RESULTS: Seventy-one patients were recruited (standard care 33; VEM 38).There were no significant group differences in the number, type or severity of complications by 3 months, and most patients (81.6%) experienced one or more complications. Falls were common, while depression was absent. The multivariate analysis showed older age (OR 1.10, 95% CI: 1.02-1.18, p = 0.009) and longer length of stay (OR 1.18, 95% CI: 1.06-1.32, p = 0.002) were associated with experiencing an immobility-related complication. CONCLUSION: Interventions that promote recovery and reduce complications may consequently reduce length of stay. The larger phase III trial currently underway may shed light on whether increasing mobilisation reduces complications after stroke.

Classification of stroke subtypes.

This article reviews published stroke subtype classification systems and offers rules and a basis for a new way to subtype stroke patients. Stroke subtyping can have different purposes, e.g. describing patients' characteristics in a clinical trial, grouping patients in an epidemiological study, careful phenotyping of patients in a genetic study, and classifying patients for therapeutic decision-making in daily practice. The classification should distinguish between ischemic and hemorrhagic stroke, subarachnoid hemorrhage, cerebral venous thrombosis, and spinal cord stroke. Regarding the 4 main categories of etiologies of ischemic stroke (i.e. atherothrombotic, small vessel disease, cardioembolic, and other causes), the classification should reflect the most likely etiology without neglecting the vascular conditions that are also found (e.g. evidence of small vessel disease in the presence of severe large vessel obstructions). Phenotypes of large cohorts can also be characterized by surrogate markers or intermediate phenotypes (e.g. presence of internal carotid artery plaque, intima-media thickness of the common carotid artery, leukoaraiosis, microbleeds, or multiple lacunae). Parallel classifications (i.e. surrogate markers) may serve as within-study abnormalities to support research findings.