Hyperglycaemia and the ischaemic brain: continuous glucose monitoring and implications for therapy.

Hyperglycaemia following acute stroke is both common and prolonged, regardless of diabetes status. A substantial body of evidence, derived from animal and human literature, has demonstrated that post-stroke hyperglycaemia has a deleterious effect upon clinical and radiological stroke outcomes. Whether intensive glycaemic manipulation positively influences the fate of ischaemic tissue remains to be shown. This article provides an overview of the prevalence, aetiology, and mechanisms of tissue injury arising as a result of post-stroke hyperglycaemia, as well as exploring the evidence from glucose-lowering treatment trials to date. Additionally, novel insights into post-stroke hyperglycaemia derived from continuous glucose monitoring are discussed. Stroke is a leading cause of death worldwide and the commonest cause of long-term disability amongst adults. Increasing evidence suggests that disordered physiological variables following acute ischaemic stroke adversely affect outcomes. Of these, post-stroke hyperglycaemia (PSH) is the most frequently recognised abnormality and is documented in up to 50% of patients at the time of stroke presentation. Importantly, a significant proportion of hyperglycaemic acute stroke patients (approximately 50%) have undiagnosed disorders of glucose metabolism, including diabetes. Animal and human data have repeatedly demonstrated that PSH negatively impacts upon the fate of ischaemic brain tissue, with greater infarct growth, higher mortality and more severe disability being consistent findings amongst hyperglycaemic stroke subjects. For these reasons, PSH represents an attractive physiological target for acute stroke therapies with potential application across broad time windows, stroke subtypes and stroke severity. In addition to providing an overview of the adverse effects of hyperglycaemia following acute ischaemic stroke, this article aims to summarise the evidence from current glucose-lowering treatment trials as well as exploring continuous glucose monitoring and the implications for future glycaemic manipulation.

Insular cortical ischemia is independently associated with acute stress hyperglycemia.

BACKGROUND AND PURPOSE: Acute poststroke hyperglycemia has been associated with larger infarct volumes and a cortical location, regardless of diabetes status. Stress hyperglycemia has been attributed to activation of the hypothalamic-pituitary-adrenal axis but never a specific cortical location. We tested the hypothesis that damage to the insular cortex, a site with autonomic connectivity, results in hyperglycemia reflecting sympathoadrenal dysregulation. METHODS: Diffusion-weighted MRI, glycosylated hemoglobin (HbA1c), and blood glucose measurements were obtained in 31 patients within 24 hours of ischemic stroke onset. Acute diffusion-weighted imaging (DWI) lesion volumes were measured, and involvement of the insular cortex was assessed on T2-weighted images. RESULTS: Median admission glucose was significantly higher in patients with insular cortical ischemia (8.6 mmol/L; n=14) compared with those without (6.5 mmol/L; n=17; P=0.006). Multivariate linear regression demonstrated that insular cortical ischemia was a significant independent predictor of glucose level (P=0.001), as was pre-existing diabetes mellitus (P=0.008). After controlling for the effect of insular cortical ischemia, DWI lesion volume was not associated with higher glucose levels (P=0.849). There was no association between HbA1c and glucose level (P=0.737). CONCLUSIONS: Despite the small sample size, insular cortical ischemia appeared to be associated with the production of poststroke hyperglycemia. This relationship is independent of pre-existing glycemic status and infarct volume. Neuroendocrine dysregulation after insular ischemia may be 1 aspect of a more generalized acute stress response. Future studies of poststroke hyperglycemia should account for the effect of insular cortical ischemia.

Basilar artery occlusion.

Basilar artery occlusion is assumed to carry a grave prognosis, with mortality rates of up to 90%. Diagnosis is often delayed, or even missed, as a result of the variety of clinical presentations seen with this condition. The pathogenesis of occlusion can be secondary to both local atherothrombosis or cardioembolism. The use of noninvasive imaging such as magnetic resonance imaging and computed tomography angiography has improved recognition of clinical syndromes associated with occlusion. Although no randomized studies have been performed, recanalization of the vascular occlusion, particularly with thrombolytic agents, appears to result in improved outcomes in selected patients. However, the optimum timing for therapy is unclear, and reperfusion therapy may need to be combined with definitive vascular treatment of underlying vascular stenosis. Increasing awareness of this condition may reveal the natural history to be more diverse than previously recognized.

Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome.

BACKGROUND AND PURPOSE: Hyperglycemia at the time of ischemic stroke is associated with increased mortality and morbidity. Animal studies suggest that infarct expansion may be responsible. The influence of persisting hyperglycemia after stroke has not previously been examined. We measured the blood glucose profile after acute ischemic stroke and correlated it with infarct volume changes using T2- and diffusion-weighted MRI. METHODS: We recruited 25 subjects within 24 hours of ischemic stroke symptoms. Continuous glucose monitoring was performed with a glucose monitoring device (CGMS), and 4-hour capillary glucose levels (BGL) were measured for 72 hours after admission. MRI and clinical assessments were performed at acute (median, 15 hours), subacute (median, 5 days), and outcome (median, 85 days) time points. RESULTS: Mean CGMS glucose and mean BGL glucose correlated with infarct volume change between acute and subacute diffusion-weighted MRI (r>or=0.60, P<0.01), acute and outcome MRI (r=0.56, P=0.01), outcome National Institutes of Health Stroke Scale (NIHSS; r>or=0.53, P<0.02), and outcome modified Rankin Scale (mRS; r>or=0.53, P=0.02). Acute and final infarct volume change and outcome NIHSS and mRS were significantly higher in patients with mean CGMS or mean BGL glucose >or=7 mmol/L. Multiple regression analysis indicated that both mean CGMS and BGL glucose levels >or=7 mmol/L were independently associated with increased final infarct volume change. CONCLUSIONS: Persistent hyperglycemia on serial glucose monitoring is an independent determinant of infarct expansion and is associated with worse functional outcome. There is an urgent need to study normalization of blood glucose after stroke.

Acute stroke thrombolysis with intravenous tissue plasminogen activator in an Australian tertiary hospital.

OBJECTIVE: To report initial experience with the use of intravenous tissue plasminogen activator (tPA) to treat acute ischaemic stroke at an Australian tertiary-care hospital. DESIGN: Retrospective audit of computerised hospital stroke database. PARTICIPANTS AND SETTING: All patients with acute ischaemic stroke treated with intravenous tPA between April 1999 and July 2002 at the Royal Melbourne Hospital, VIC. MAIN OUTCOME MEASURES: Times from stroke onset to arrival at the emergency department (ED) and treatment; rates of symptomatic intracerebral haemorrhage (ICH); clinical outcome at three months; and violations of treatment protocol. RESULTS: Of 932 patients admitted with ischaemic stroke, 30 were treated with intravenous tPA. Median time from stroke onset to tPA treatment was 2 h 48 min, and median door-to-needle time was 1 h 49 min. Door-to-needle time improved in the last 12 months of the audit, with four of 15 patients achieving the recommended 60 min. Eleven patients (37%) had excellent clinical outcomes at three-month follow-up (modified Rankin score, 0-1), and 15 (50%) were functionally independent (score, 0-2). Mortality rate was 10%, similar to that of all ischaemic stroke patients during the audit period. Two patients (7%) had symptomatic ICH. Treatment deviated from protocol in seven patients (23%), five of whom received tPA over three hours after stroke onset. CONCLUSION: Rates of favourable outcomes and symptomatic ICH at our hospital were similar to those achieved in international phase III and IV trials in specialised centres.

Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study.

Controversy exists whether acute hyperglycemia is causally associated with worse stroke outcome or simply reflects a more severe stroke. In reversible ischemia models, hyperglycemia is associated with lactic acidosis and conversion of penumbral tissue to infarction. However, the relationship between hyperglycemia, lactic acidosis, and stroke outcome has not been explored in humans. Sixty-three acute stroke patients were prospectively evaluated with serial diffusion-weighted and perfusion-weighted magnetic resonance imaging and acute blood glucose measurements. Patients with hypoperfused at-risk tissue were identified by acute perfusion-diffusion lesion mismatch. As a substudy, acute and subacute magnetic resonance spectroscopy was performed in the 33 most recent patients to assess the relationship between acute blood glucose and lactate production in the ischemic region. In 40 of 63 patients with acute perfusion-diffusion mismatch, acute hyperglycemia was correlated with reduced salvage of mismatch tissue from infarction, greater final infarct size, and worse functional outcome. These correlations were independent of baseline stroke severity, lesion size, and diabetic status. Furthermore, higher acute blood glucose in patients with perfusion-diffusion mismatch was associated with greater acute-subacute lactate production, which, in turn, was independently associated with reduced salvage of mismatch tissue. In contrast, acute blood glucose levels in nonmismatch patients did not independently correlate with outcome measures, nor was there any acute-subacute increase in lactate in this group. Acute hyperglycemia increases brain lactate production and facilitates conversion of hypoperfused at-risk tissue into infarction, which may adversely affect stroke outcome. These findings support the need for randomized controlled trials of aggressive glycemic control in acute stroke.

The influence of diabetes mellitus and hyperglycaemia on stroke incidence and outcome.

Diabetes mellitus is a complex metabolic syndrome with significant effects on the systemic and cerebral vasculature. The incidence and severity of ischaemic stroke are increased by the presence of diabetes, and outcome from stroke is poorer. More than one third of patients admitted with acute stroke are hyperglycaemic at presentation. Reasons for the altered prognosis in diabetes associated stroke are multifactorial. A direct influence of hyperglycaemia at the time of ischaemia is likely to be important. The use of novel methods to delineate stroke topography and pathophysiology such as MR spectroscopy, diffusion and perfusion weighted MRI appear helpful in delineating the effects of hyperglycaemia on stroke pathophysiology. Randomised clinical trials to determine optimal management for patients with hyperglycaemia following stroke are ongoing. Such trials will determine if aggressive control of acute hyperglycaemia following stroke has similar benefits to that observed following acute myocardial infarction. Clinicians responsible for stroke patients should be aware of the importance of adequate glycaemic control in both primary and secondary prevention of stroke.