Kyra J. Becker

Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use

Neuroprotection and brain repair in patients after acute brain damage are still major unfulfilled medical needs. Pharmacological treatments are either ineffective or confounded by adverse effects. Consequently, endogenous mechanisms by which the brain protects itself against noxious stimuli and recovers from damage are being studied. Research on preconditioning, also known as induced tolerance, over the past decade has resulted in various promising strategies for the treatment of patients with acute brain injury. Several of these strategies are being tested in randomised clinical trials. Additionally, research into preconditioning has led to the idea of prophylactically inducing protection in patients such as those undergoing brain surgery and those with transient ischaemic attack or subarachnoid haemorrhage who are at high risk of brain injury in the near future. In this Review, we focus on the clinical issues relating to preconditioning and tolerance in the brain; specifically, we discuss the clinical situations that might benefit from such procedures. We also discuss whether preconditioning and tolerance occur naturally in the brain and assess the most promising candidate strategies that are being investigated.

Withdrawal of support in intracerebral hemorrhage may lead to self-fulfilling prophecies

Background: Withdrawal of support in patients with severe brain injury invariably leads to death. Preconceived notions about futility of care in patients with intracerebral hemorrhage (ICH) may prompt withdrawal of support, and modeling outcome in patient populations in whom withdrawal of support occurs may lead to self-fulfilling prophecies. Methods: Subjects included consecutive patients with supratentorial ICH. Radiographic characteristics of the hemorrhage, clinical variables, and neurologic outcome were assessed. Attitudes about futility of care were examined among members of the departments of neurology and neurologic surgery through a written survey and case presentations. Results: There were 87 patients with supratentorial ICH; overall mortality was 34.5% (30/87). Mortality was 66.7% (18/27) in patients with Glasgow Coma Score ≤8 and ICH volume >60 cm3. Medical support was withdrawn in 76.7% (23/30) of patients who died. Inclusion of a variable to account for the withdrawal of support in a model predicting outcome negated the predictive value of all other variables. Patients undergoing surgical decompression were unlikely to have support withdrawn, and surgery was less likely to be performed in older patients (p < 0.01) and patients with left hemispheric hemorrhage (p = 0.04). Survey results suggested that practitioners tend to be overly pessimistic in prognosticating outcome based upon data available at the time of presentation. Conclusions: The most important prognostic variable in determining outcome after ICH is the level of medical support provided. Withdrawal of support in patients felt likely to have a “poor outcome” biases predictive models and leads to self-fulfilling prophecies. Our data show that individual patients in traditionally “poor outcome” categories can have a reasonable neurologic outcome when treated aggressively.

Primary Prevention of Ischemic Stroke A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association

Stroke ranks as the third leading cause of death in the United States. It is now estimated that there are more than 700 000 incident strokes annually and 4.4 million stroke survivors.1 2 The economic burden of stroke was estimated by the American Heart Association to be

Moyamoya disease in Washington State and California

51 billion (direct and indirect costs) in 1999.3 Despite the advent of treatment of selected patients with acute ischemic stroke with tissue plasminogen activator and the promise of other experimental therapies, the best approach to reducing the burden of stroke remains prevention.4 5 High-risk or stroke-prone individuals can be identified and targeted for specific interventions.6 This is important because epidemiological data suggest a substantial leveling off of prior declines in stroke-related mortality and a possible increase in stroke incidence.7 8 The Stroke Council of the American Heart Association formed an ad hoc writing group to provide a clear and concise overview of the evidence regarding various established and potential stroke risk factors. The writing group was chosen based on expertise in specific subject areas, and it used literature review, reference to previously published guidelines, and expert opinion to summarize existing evidence and formulate recommendations (Table 1⇓). View this table: Table 1. Levels of Evidence and Grading of Recommendations As given in Tables 2 through 4⇓⇓⇓, risk factors or risk markers for a first stroke were classified according to potential for modification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (well documented, less well documented).5 The tables give the estimated prevalence, population attributable risk, relative risk, and risk reduction with treatment for each factor when known. Population attributable risk reflects the proportion of ischemic strokes in the population that can be attributed to a particular risk factor and is given by the formula 100×[prevalence(relative risk−1)/prevalence(relative risk−1)+1]). …

Treatment of hyperglycemia in ischemic stroke (THIS): A randomized pilot trial

The authors identified 298 diagnoses of moyamoya in California and Washington from hospital discharge databases during the period 1987 to 1998. The incidence was 0.086/100,000 persons. The ethnicity-specific incidence rate ratios compared to whites were 4.6 (95% CI: 3.4 to 6.3) for Asian Americans, 2.2 (95% CI: 1.3 to 2.4) for African Americans, and 0.5 (95% CI: 0.3 to 0.8) for Hispanics. The incidence of moyamoya in Washington and California was lower than reported in Japan, but the rate among U.S. Asians is similar.

Extravasation of Radiographic Contrast Is an Independent Predictor of Death in Primary Intracerebral Hemorrhage

Background and Purpose— Hyperglycemia may worsen brain injury during acute cerebral infarction. We tested the feasibility and tolerability of aggressive hyperglycemia correction with intravenous insulin compared with usual care during acute cerebral infarction. Methods— We conducted a randomized, multicenter, blinded pilot trial for patients with cerebral infarction within 12 hours after onset, a baseline glucose value ≥8.3 mmol/L (≥150 mg/dL), and a National Institutes of Health Stroke Scale score of 3 to 22. Patients were randomized 2:1 to aggressive treatment with continuous intravenous insulin or subcutaneous insulin QID as needed (usual care). Target glucose levels were <7.2 mmol/L (<130 mg/dL) in the aggressive-treatment group and <11.1 mmol/L (<200 mg/dL) in the usual-care group. Glucose was monitored every 1 to 2 hours, and the protocol treatments continued for up to 72 hours. Final clinical outcomes were assessed at 3 months. Results— We randomized 46 patients (31 to aggressive treatment and 15 to usual care). All patients in the aggressive-treatment group and 11 (73%) in the usual-care group had diabetes (P=0.008). Glucose levels were significantly lower in the aggressive-treatment group throughout protocol treatment (7.4 vs 10.5 mmol/L [133 vs 190 mg/dL], P<0.001). Hypoglycemia <3.3 mmol/L (<60 mg/dL) occurred only in the aggressive-treatment group (11 patients, 35%), 4 (13%) of whom had brief symptoms, including only 1 (3%) neurologic. Final clinical outcomes were nonsignificantly better in the aggressive-treatment group. Conclusions— The intravenous insulin protocol corrected hyperglycemia during acute cerebral infarction significantly better than usual care without major adverse events and should be investigated in a clinical efficacy trial.

Community-based education improves stroke knowledge.

BACKGROUND AND PURPOSE Hematomas that enlarge following presentation with primary intracerebral hemorrhage (ICH) are associated with increased mortality, but the mechanisms of hematoma enlargement are poorly understood. We interpreted the presence of contrast extravasation into the hematoma after CT angiography (CTA) as evidence of ongoing hemorrhage and sought to identify the clinical significance of contrast extravasation as well as factors associated with the risk of extravasation. METHODS We reviewed the clinical records and radiographic studies of all patients with intracranial hemorrhage undergoing CTA from 1994 to 1997. Only patients with primary ICH were included in this study. Univariate and multivariate logistic regression analyses were performed to determine the associations between clinical and radiological variables and the risk of hospital death or contrast extravasation. RESULTS Data were available for 113 patients. Contrast extravasation was seen in 46% of patients at the time of CTA, and the presence of contrast extravasation was associated with increased fatality: 63.5% versus 16.4% in patients without extravasation (P=0.011). There was a trend toward a shorter time (median+/-SD) from symptom onset to CTA in patients with extravasation (4.6+/-19 hours) than in patients with no evidence of extravasation (6.6+/-28 hours; P=0.065). Multivariate analysis revealed that hematoma size (P=0.022), Glasgow Coma Scale (GCS) score (P=0.016), extravasation of contrast (P=0.006), infratentorial ICH (P=0.014), and lack of surgery (P<0.001) were independently associated with hospital death. Variables independently associated with contrast extravasation were hematoma size (P=0.024), MABP >120 mm Hg (P=0.012), and GCS score of </=8 (P<0.005). CONCLUSIONS Contrast extravasation into the hematoma after ICH is associated with increased fatality. The risk of contrast extravasation is increased with extreme hypertension, depressed consciousness, and large hemorrhages. If contrast extravasation represents ongoing hemorrhage, the findings in this study may have implications for therapy of ICH, particularly with regard to blood pressure management.

Antibody to the α4 Integrin Decreases Infarct Size in Transient Focal Cerebral Ischemia in Rats

Background and Purpose: Despite advances in stroke therapy, the public remains uninformed about stroke, and few stroke patients present to the hospital in time to receive treatment. Health education campaigns can increase community awareness and may decrease time to hospital presentation among stroke patients. Methods: We conducted a community-based education campaign utilizing television and newspapers to inform the residents of King County, Wash., USA, about stroke and the need to call 911. The effectiveness of the campaign was assessed, using a pretest-posttest design, through telephone interviews with residents of King County. Results: Prior to the education campaign, 59.6% of persons in King County could name a risk factor for stroke, but only 45.2% knew that the brain was the organ of injury. And while 68.2% of persons stated that they would call 911 in the event of stroke, only 38.6% could name a symptom of stroke. The knowledge deficit was greatest among Asian-Americans, men, the less educated and low-income residents. There was a significant increase in stroke knowledge following the education campaign; respondents were 52% (p = 0.005) more likely to know a risk factor for stroke and 35% (p = 0.032) more likely to know a symptom of stroke after the campaign. Conclusions: Baseline knowledge about stroke among the public is poor, but can be increased through public education campaigns.

Brief Psychosocial–Behavioral Intervention With Antidepressant Reduces Poststroke Depression Significantly More Than Usual Care With Antidepressant Living Well With Stroke: Randomized, Controlled Trial

Background and Purpose—Inflammation, a process that involves neutrophils, lymphocytes, and monocytes, contributes to cerebral ischemic injury. Blockade of neutrophil adhesion to endothelium improves outcome after experimental stroke. In this study we sought to assess the contribution of lymphocytes and monocytes to ischemic brain injury. Methods—Male Lewis rats underwent 3 hours of middle cerebral artery occlusion followed by 45 hours of reperfusion. Two hours after the onset of ischemia, one group of animals received an intraperitoneal injection of antibodies to the α4 integrin (n=16); another group was injected with an isotype control antibody (n=11). Neurological examination, body temperature, and body weight were assessed at different time points after stroke. Animals were killed 48 hours after the onset of ischemia for determination of infarct volume and leukocyte counts. Results—There were no significant differences in body temperature or weight at any time. Neurological scores (deficits) were signi...

Sensitization to brain antigens after stroke is augmented by lipopolysaccharide.

Background and Purpose— Depression after stroke is prevalent, diminishing recovery and quality of life. Brief behavioral intervention, adjunctive to antidepressant therapy, has not been well evaluated for long-term efficacy in those with poststroke depression. Methods— One hundred one clinically depressed patients with ischemic stroke within 4 months of index stroke were randomly assigned to an 8-week brief psychosocial–behavioral intervention plus antidepressant or usual care, including antidepressant. The primary end point was reduction in depressive symptom severity at 12 months after entry. Results— Hamilton Rating Scale for Depression raw score in the intervention group was significantly lower immediately posttreatment (P<0.001) and at 12 months (P=0.05) compared with control subjects. Remission (Hamilton Rating Scale for Depression <10) was significantly greater immediately posttreatment and at 12 months in the intervention group compared with the usual care control. The mean percent decrease (47%±26% intervention versus 32%±36% control, P=0.02) and the mean absolute decrease (−9.2±5.7 intervention versus −6.2±6.4 control, P=0.023) in Hamilton Rating Scale for Depression at 12 months were clinically important and statistically significant in the intervention group compared with control. Conclusion— A brief psychosocial–behavioral intervention is highly effective in reducing depression in both the short and long term.