Pathophysiology of post-stroke hyperglycaemia and brain arterial patency

The pathophysiology of acute post-stroke hyperglycaemia (PSH) is important as hyperglycaemia affects the majority of stroke patients, and is consistently associated with poorer outcome in terms of survival, disability and markers of brain injury such as infarct expansion. There appears to be an interaction between brain arterial patency and hyperglycaemia that has not been fully characterised. This thesis initially reviews the literature on hyperglycaemia and stroke before focusing on animal models of PSH and clinical trials of insulin treatment for PSH in two systematic reviews with meta-analysis. The thesis then looks at the relationship between glucose profiles and clinical outcome in a historical population receiving IV thrombolysis for acute ischaemic stroke, specifically exploring alternative indices of glycaemic state to compare the optimal predictive index for functional outcome as measured by the modified Rankin scale. The main body of the thesis details a prospective observational clinical study which recruited 108 patients within 6 hours of acute ischaemic stroke. These patients had careful monitoring of blood glucose levels over a 48 hour period and detail brain imaging including CT perfusion scanning to examine the ischaemic penumbra, CT angiography on admission and at 24-48 hours to document brain arterial patency with follow-up CT brain imaging to assess outcome infarct volume. The relationship between 48 hour blood glucose profiles, clinical outcome and imaging findings is then explored. The main findings of the thesis are summarized below. · Animal models of PSH have shown that hyperglycaemia exacerbates infarct volume in MCA occlusion models but studies are heterogeneous, and do not address the common clinical problem of PSH because they have used either the streptozotocin model of type I diabetes or extremely high glucose loads. · Animal models show that insulin has a non-significant and significantly heterogeneous effect on infarct growth. 3 · Clinical trials of insulin for post stroke hyperglycaemia have shown no benefit in terms of improved functional outcomes or mortality. Insulin is associated with an increased risk of hypoglycaemia. · In a historical cohort mean capillary blood glucose over 48 hours was more predictive of clinical outcome that admission blood glucose or two consecutive elevated glucose measurements. · A high proportion of acute stroke patients have a blood glucose level above 7mmol/L within 6 hours of onset. Different patterns of blood glucose levels define different populations. · Higher admission and mean glucose levels correlate with larger infarct volumes. Larger core perfusion lesion volumes are associated with a greater risk of mortality. Admission hyperglycaemia is more harmful than hyperglycaemia after 6 hours. · In patients with angiographic evidence of an arterial occlusion infarct volume varies significantly with glycaemic status. In some populations late hyperglycaemia is associated with better imaging outcomes. · Tandem occlusions are associated with bad outcomes after ischaemic stroke

Iodinated contrast media and cerebral hemorrhage after intravenous thrombolysis

<p>Background and Purpose: Iodinated contrast is increasingly used in CT perfusion or angiographic examinations in acute stroke. Increased risk of intracranial hemorrhage (ICH) complicating microcatheter contrast injections has recently been reported in the second Interventional Management of Stroke (IMS 2) trial with contrast toxicity potentially contributory.</p> <p>Methods: We reviewed clinical and radiological data on all patients treated with intravenous alteplase at a single center between May 2003 and November 2008.</p> <p>Results: Of 312 patients treated with intravenous alteplase, 69 (22.1%) received intravenous iodinated contrast in volumes between 50 and 150 mL. Incidence of symptomatic ICH defined as per European Cooperative Acute Stroke Study 2 was 16 of 312 (5.1%; 95% CI, 2.7% to 7.6%); among patients not given contrast, it was 12 of 243 (4.9%; 2.2% to 7.7%) compared with 4 of 69 (5.8%; 0.3% to 11.3%) in those given contrast. Incidence of symptomatic ICH defined as per Safe Implementation of Thrombolysis in Stroke-MOnitoring Study (SITS-MOST) criteria was 12 of 312 (3.9%; 1.7% to 6%), 9 of 243 (3.7%; 1.3% to 6%) among those not given contrast, and 3 of 69 (4.4%; 95% CI, -0.5% to 9.2%) among those given contrast. Patients with symptomatic ICH were older, had higher pretreatment National Institutes of Health Stroke Scale, and blood glucose than those without symptomatic ICH. In logistic regression analysis, pretreatment blood glucose was the only significant predictor of symptomatic ICH by either definition (OR, 1.23; 95% CI, 1.03 to 1.48 per mmol/L increment; P=0.024). Contrast administration or dose was not associated with symptomatic ICH.</p> <p>Conclusions: Intravenous iodinated contrast in doses typically required for CT angiography and perfusion imaging was not associated with symptomatic intracranial hemorrhage in patients treated with alteplase.</p&gt

Systematic review of prediction models in relapsing remitting multiple sclerosis

The natural history of relapsing remitting multiple sclerosis (RRMS) is variable and prediction of individual prognosis challenging. The inability to reliably predict prognosis at diagnosis has important implications for informed decision making especially in relation to disease modifying therapies. We conducted a systematic review in order to collate, describe and assess the methodological quality of published prediction models in RRMS. We searched Medline, Embase and Web of Science. Two reviewers independently screened abstracts and full text for eligibility and assessed risk of bias. Studies reporting development or validation of prediction models for RRMS in adults were included. Data collection was guided by the checklist for critical appraisal and data extraction for systematic reviews (CHARMS) and applicability and methodological quality assessment by the prediction model risk of bias assessment tool (PROBAST). 30 studies were included in the review. Applicability was assessed as high risk of concern in 27 studies. Risk of bias was assessed as high for all studies. The single most frequently included predictor was baseline EDSS (n = 11). T2 Lesion volume or number and brain atrophy were each retained in seven studies. Five studies included external validation and none included impact analysis. Although a number of prediction models for RRMS have been reported, most are at high risk of bias and lack external validation and impact analysis, restricting their application to routine clinical practice

Longitudinal retinal imaging study of newly diagnosed relapsing-remitting multiple sclerosis in Scottish population: baseline and 12 months follow-up profile of FutureMS retinal imaging cohort

Objective: Multiple sclerosis (MS) is an inflammatory degenerative condition of central nervous system. The disease course and presentation of MS is highly heterogeneous. Advanced retinal imaging techniques such as optic coherence tomography (OCT) can capture abnormalities of anterior visual pathway with high resolution, which may contribute greater insights into the pathophysiology of MS. Methods: People with newly diagnosed relapsing-remitting MS were recruited for FutureMS retinal imaging study from two study centres in Scotland. The baseline visit was completed within 6 months of diagnosis with initial follow-up 12 months after the baseline visit. The assessments included in FutureMS retinal imaging study were visual acuity test, self-reported eye questionnaire and OCT scan. Results: A total of 196 FutureMS participants completed the retinal imaging study of FutureMS with 185 participants at M0 and 155 at M12. A total of 144 participants completed both M0 and M12 visits. At the whole cohort level, the distribution of retinal measures is generally consistent between baseline and follow-up. Conclusion: The FutureMS retinal imaging study aims to demonstrate that patient with MS present with different extent of retinal abnormalities that can be captured by retinal imaging modalities such as OCT soon after diagnosis. These changes may sensitively mirror the brain atrophy or serve as predictors for disease activity. By developing sensitive, quantifiable and objective retinal biomarkers, FutureMS retinal imaging study will provide an opportunity to stratify patient with MS at an early stage and support future therapeutic strategies for a better outcome

MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis, by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation (MTsat) and neurite orientation dispersion and density imaging (NODDI) diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 vs 0.57, difference 0.036, 95% CI 0.029 to 0.043, p < 0.001). Lesion volume (Spearman’s rho rs= 0.38, p < 0.001) and g-ratio (rs= 0.24 p < 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) (11/23 [48%] versus 2/15 [13%] p < 0.05). These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity, and help to identify individuals with a high degree of axonal damage at disease onset. York, Martin et al. simultaneously measured g-ratio and plasma neurofilament in 73 relapsing-remitting multiple sclerosis patients at diagnosis using advanced MRI and single molecule ELISA. They demonstrate that g-ratio of cerebral white matter lesions varies at diagnosis, and show that high g-ratio of lesions is associated with elevated plasma neurofilament

Neurological Scottish neologisms

No abstract available

Derivation and evaluation of thresholds for core and tissue at risk of infarction using CT perfusion

Background and purpose: Computed tomography perfusion provides information on tissue viability according to proposed thresholds. We evaluated thresholds for ischemic core and tissue at risk and subsequently tested their accuracy in independent datasets.<p></p> Materials and methods: Tissue at risk was evaluated in patients with persistent arterial occlusions, and ischemic core thresholds in patients with recanalization and major clinical improvement. Scans were randomly allocated to derivation or validation groups for tissue at risk and core analysis. Optimum thresholds using mean transit time (MTT), cerebral blood flow (CBF), cerebral blood volume, and delay time (DT) were assessed.<p></p> Results: Absolute MTT, relative MTT and DT were best derived predictors of tissue at risk with thresholds of ≥7 seconds, ≥125%, and ≥2 seconds respectively. DT ≥ 2 seconds was the best predictor in the validation dataset (95% agreement levels = −44 to +30 mL, Bias = −6.9). Absolute and relative MTT were the best derived predictors of infarct volume in the core group (8 seconds and 125% respectively) but relative CBF of ≤45% performed best in the core validation dataset.<p></p> Conclusion: Time-based perfusion thresholds perform well as predictors of tissue at risk of infarction with DT the best predictor. Relative CBF was the best predictor of ischemic core. Evaluation in larger populations is needed to confirm the performance of tissue viability thresholds.<p></p&gt