Cerebral venous thrombosis and heparin-induced thrombocytopenia in an 18-year old male with severe ulcerative colitis.

The risk of thromboembolism is increased in inflammatory bowel disease and its symptoms may be overlooked. Furthermore, its treatment can be complex and is not without complications. We describe a case of an adolescent boy who developed a cerebral sinus venous thrombosis during a relapse of his ulcerative colitis and who, while on treatment with heparin, developed heparin-induced thrombocytopenia (HIT). The treatment was then switched to fondaparinux, a synthetic and selective inhibitor of activated factor X.

The Virtual International Stroke Trials Archive.

BACKGROUND AND PURPOSE: Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses. METHODS: Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing. RESULTS: Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on >15,000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 69+/-12 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials. CONCLUSIONS: This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning.

Salivary cortisol, a biological marker of stress, is positively associated with 24-hour systolic blood pressure in patients with acute ischaemic stroke.

BACKGROUND/AIM: The cause of elevated blood pressure (BP) in acute stroke is unknown. Stress is often suggested as a main contributing factor. We aimed to investigate the relationship between BP and stress in patients with acute stroke. METHODS: 58 patients with clinical symptoms of stroke were recruited prospectively after exclusion of haemorrhage by CT scan within 14 h and 15 min (mean) after symptom onset (range 2 h and 45 min-23 h and 40 min). The mean age of the patients was 66 years (range 39-86 years), and the mean National Institute of Health Stroke Scale score was 7 (range 1-26). BP and pulse rate were recorded by non-invasive automatic monitoring hourly for 24 h. Stress was evaluated by testing the level of salivary cortisol. Four samples of saliva were obtained at inclusion, on the evening of the inclusion day (20.00-22.00 h), on the morning of the next day (7.00-9.00 h) and on the afternoon of the inclusion day/next day (15.00-17.00 h) within 24 h after inclusion in the study. Logarithmic transformation was done for cortisol levels. RESULTS: The 24-hour mean cortisol level (geometric mean 13.6 nmol/l) was related to 24-hour mean systolic BP [SBP; r = 0.36, p = 0.01, multivariate p = 0.02], mean night-time (22.00-6.00 h) SBP (r = 0.43, p = 0.001, multivariate p < 0.005) and mean night-time diastolic BP (r = 0.31, p = 0.02, multivariate p = 0.02). Cortisol levels at inclusion (r = 0.31, p = 0.02, multivariate p = 0.05 for 24-hour SBP) and in the evening were also statistically significantly related to the above BP variables. The morning cortisol (r = 0.28, p = 0.04, multivariate p = 0.04) was related to night-time SBP. CONCLUSIONS: Salivary cortisol was positively correlated with 24-hour SBP and night-time BP, suggesting that stress is a contributing factor for high BP in acute stroke.

Neuroprotection in cerebral ischaemia: facts and fancies--the need for new approaches.

'Neuroprotection' is a term used to describe the putative effect of interventions protecting the brain from pathological damage. In occlusive stroke, the concept of neuroprotection involves inhibition of a cascade of pathological molecular events occurring under ischaemia and leading to calcium influx, activation of free radical reactions and cell death. This article will summarize neuroprotection trials to date, some facts and fancies about neuroprotection, ischaemic pathophysiology and possible reasons for the apparent failure of human neuroprotective stroke trials. FACTS: In the acute stage of occlusive stroke, moderate reduction of blood flow results in a 'penumbra' of brain cells, often surrounding a core infarct, in which brain cells survive for a few hours but gradually die if reperfusion is not established. Increased knowledge of the complex pathophysiology in acute ischaemic stroke has led to the development of a great number of candidates for neuroprotective interventions. Many neuroprotective agents have proven efficacious in animal models, but so far no human study has shown a statistically significant benefit in patients with acute ischaemic stroke on primary endpoint measures. Some neuroprotective agents show beneficial effects on post hoc analyses, and some studies are still ongoing. FANCIES: In the early years of neuroprotective studies in stroke, it was thought that a drug with almost no adverse effects could be given by ambulance staff on the way to hospital and induce a clinically significant effect on outcome. Since there were only benefits and no risks, diagnostic skills by neurologists and neuroradiological evaluations would no longer be required. WHY HAVE NEUROPROTECTIVE AGENTS FAILED IN HUMAN STROKE TRIALS? There are several possible explanations why neuroprotective trials have been unable to prove an effect in addition to the eventuality that the basic concept is wrong. The effects of neuroprotective agents on infarct size are time dependent, and treatment has often been initiated much later than in successful experimental stroke models. Insufficient doses of the drugs and slow availability of the drug at the target area may be other explanations. Too small sample sizes in trials and imbalance of prognostically important baseline variables are examples of shortcomings in trial methodology. WHAT CAN BE DONE? FUTURE NEW APPROACHES: IN ANIMAL MODELS, preclinical testing of neuroprotective candidates should be standardized. Conventional stroke models with young and healthy animals may be replaced by older animals with common co-morbidity such as atherosclerosis. Highly effective new neuroprotective agents need to be discovered, and combination therapies should be tried. IN CLINICAL TRIALS, the greatest chances of success may be with neuroprotective concepts involving mechanisms in both ischaemic and reperfusion pathophysiology, in combination with a thrombolytic therapy protocol. Neuroprotective agents, possibly combinations of agents, should preferably approach several of these mechanisms. Treatments should be initiated early, at least within 3 h after stroke onset, by an intravenous route. The selected compound(s) should easily pass the blood-brain barrier. Neuroprotective agents shown to be highly effective in stroke models should be preferred, and doses used experimentally should be used also in the clinical setting. Trials should use randomization techniques, which reduce imbalances of prognostically important baseline variables, and the estimated sample size of a trial should be based on expectations of a modest clinical effect.

Pharmacokinetics of dexamphetamine in acute stroke.

Pharmacokinetics of dexamphetamine was studied in 26 patients with cerebral infarct, aged 37 to 84 years. Capsules were administered orally twice daily (at 8 am and 12 am) in three doses (2.5 mg, 5 mg, and 10 mg) for 5 consecutive days (day 1 to day 5). Blood samples were collected immediately before and 1, 2, 3, 4, 5, 6, 7, 8, and 9 hours after first administration on day 1 and before, and 4 and 8 hours after administration on days 2 through 5. The dose normalized area under the plasma concentration time curve, AUC/mg/kg, was only correlated with s-creatinine (P = 0.013) but not with age, sex, body mass index, neurologic prognosis, or dose (mg/kg), as established by multiple stepwise linear regression. The median terminal half life time was 14.3 hours (inter quartile range, IQR: 11.9-6.9), 13.1 (IQR: 10.8-15.9) and 14.0 (IQR: 7.4-16.4) in the 2.5 mg, 5 mg, and 10 mg groups, respectively. The median maximal plasma concentration (Cmax) was 6.6 ng/mL (IQR: 5.1-7.0), 11.6 (IQR: 7.8-12.8), and 16.9 (IQR: 14.9-20.2) in the 2.5 mg, 5 mg, and the 10 mg groups, respectively. Differences in Cmax between the 2.5 mg and 10 mg group were significant (P < 0.001). The median time to Cmax (Tmax) was 1.83 hours (IQR: 1.79-3.94), 2.59 (IQR: 1.32-3.83), and 3.86 (IQR: 1.82-5.77) in the 2.5, 5, and 10 mg groups, respectively. In the present patient population, a predetermined AUC value can be obtained by a dosing regimen of dexamphetamine based on body weight (ie, mg/kg), with precautions for patients with elevated s-creatinine.

European Stroke Initiative Recommendations for Stroke Management-update 2003.

This article represents the update of 'European Stroke Initiative Recommendations for Stroke Management', first published in this Journal in 2000. The recommendations are endorsed by the 3 European societies which are represented in the European Stroke Initiative: the European Stroke Council, the European Neurological Society and the European Federation of Neurological Societies.

Intensive early physiotherapy combined with dexamphetamine treatment in severe stroke: a randomized, controlled pilot study.

BACKGROUND: The most severely disabled stroke patients are often excluded from studies evaluating effects of physiotherapy. This study intended to investigate the effect of an increased intensity of physiotherapy in combination with dexamphetamine the first week after ischemic stroke in patients with an impaired level of consciousness and severe motor dysfunction. METHODS: Thirty patients were enrolled within 96 h after onset of symptoms. Patients were randomized to 30-45 min of physiotherapy twice daily or to maximally 15 min per day for 5 days. All patients received dexamphetamine to achieve alertness. Functional outcome measures were assessed at baseline, the day after treatment discontinuation, and 3 and 12 months after stroke onset. Residence of living was registered at long-term follow-ups. RESULTS: No statistically significant differences were seen between groups in the outcomes measured at any time point. However, both groups improved over time in all outcomes at 3 and 12 months (p < 0.05), except for sensory functions at 3 months and motor functions at 12 months. The number of patients needed to treat (NNT) to achieve the desired improvement in Lindmark motor score was 8, with the 95% CI being NNT(harm) 10 to NNT(beneficial) 3. The fraction of patients who died was the same in both treatment groups, 47% (95% CI 28-65%). CONCLUSIONS: An increased intensity of physiotherapy in combination with dexamphetamine during the first week after stroke onset did not affect short- or long-term outcome in this limited sample of patients with severe stroke.

[Recommendations by the Swedish Quality Board for Carotid Surgery. Ultrasound good preoperative method for evaluating degree of carotid stenosis]. / Rekommendationer från Svenska kvalitetskommittén för karotiskirurgi. Ultraljud bra preoperativ metod för gradering av karotisstenos.

The estimated degree of carotid stenosis is decisive for the selection of patients who would benefit from surgical treatment. Carotid thrombendarterectomy is recommended in patients with symptomatic > or = 80 procent internal carotid artery stenosis (ECST method). Many vascular centers now often rely entirely on duplex ultrasonography to select the patients for carotid surgery. The results of a recently published Swedish multicenter study (Jogestrand et al., Eur J Vasc Endovasc Surg 2002; 23:510-8) demonstrate that certain technical aspects of the ultrasound examination are of importance for the estimation of the degree of stenosis. Based on these results, the Swedish Quality Board for Carotid Surgery recommends the use of Doppler angle range specific cut off points for the peak systolic velocity in the internal carotid artery for identification of high-grade internal carotid artery stenosis: These cut off points are > or = 2.1 m/s for insonation angles of 0-49 degrees and > or = 3.2 m/s for angles 50-60 degrees. The angle of insonation should be kept as small as possible and should always be stated in the investigators report.

Effects of blood pressure lowering in the acute phase of total anterior circulation infarcts and other stroke subtypes.

BACKGROUND: Lowering of blood pressure (BP) in the acute phase of stroke is reported both to worsen and to improve the outcome. To investigate whether heterogeneity exists between stroke subtypes in the response to BP lowering, we analysed data from the Intravenous Nimodipine West European Stroke Trial (INWEST). METHODS: INWEST enrolled acute ischaemic stroke patients within 24 h (n = 295) to the following groups: placebo (n = 100), 1 mg/h nimodipine (n = 101) or 2 mg/h nimodipine (n = 94). Patients were retrospectively classified as total anterior circulation infarct (TACI) (i.e. hemiparesis + hemianopia + dysphasia) and non-TACI (exclusion of any one of these). Main outcome measures were neurological (Orgogozo) and functional (Barthel) scores at day 21. RESULTS: 106 patients were labelled as TACI and 62 as non-TACI. No significant difference in BP was observed between the TACI and non-TACI subtypes at baseline, nor did the subtypes differ in BP course within the treatment groups. A higher proportion of non-TACI patients received postrandomisation antihypertensive agents in addition to the study drug compared with TACI patients (55% non-TACI vs. 26% TACI, p < 0.005). For TACI patients, there was no outcome difference between the placebo- and nimodipine-treated groups. For non-TACI patients, placebo had a significantly better neurological (p = 0.004) and functional (p = 0.04) outcome than the high-dose nimodipine group. In multivariate analysis for TACI patients, BP reduction and nimodipine treatment had no relation with outcome. Baseline stroke severity (p < 0.005) was the only significant predictor of the outcome at day 21. For non-TACI patients, diastolic BP (DBP) reduction (p = 0.03) and nimodipine treatment (p = 0.001) were related to neurological deterioration and nimodipine treatment (p = 0.01) to functional deterioration. Systolic BP reduction was associated with neurological (p < 0.005) and functional improvement (p = 0.01). Baseline stroke severity (p < 0.005) was related to both neurological and functional outcome. CONCLUSION: BP lowering and nimodipine treatment had no significant effect on outcome for TACI patients. For non-TACI patients, DBP lowering worsened the neurological outcome and high-dose nimodipine worsened both the neurological and functional outcome.

Safety of dexamphetamine in acute ischemic stroke: a randomized, double-blind, controlled dose-escalation trial.

BACKGROUND AND PURPOSE: Amphetamine is reported to enhance recovery after experimental stroke, but results from the first few trials in humans are inconclusive. Limited information is available on treatment safety. This study intended to investigate the safety and tolerability of dexamphetamine in patients with acute cerebral ischemia. METHODS: Forty-five patients with cerebral ischemia were enrolled within 72 hours after onset of symptoms. Patients were randomized to 1 of 3 dose levels (2.5, 5, or 10 mg orally twice daily) or placebo for 5 consecutive days. Adverse events, blood pressure, heart rate, body temperature, consciousness level, and functional outcome measures were followed up daily during treatment. Follow-ups were made at day 7 and 1 and 3 months after stroke. RESULTS: Mean systolic and diastolic blood pressures and heart rate increased 14 mm Hg, 8 mm Hg, and 9 bpm, respectively, with dexamphetamine treatment compared with placebo (P< or =0.01). There was no difference between dexamphetamine and placebo regarding adverse events, body temperature, or consciousness level. During treatment, there was a benefit of dexamphetamine in neurological and functional outcome (P<0.05), but differences were not maintained at follow-up. CONCLUSIONS: Overall, dexamphetamine was safe and well tolerated by patients with acute cerebral ischemia, but blood pressure and heart rate increased during treatment in comparison to placebo. These observations may be important in the future planning of amphetamine trials because changes in these variables have been observed to interfere with clinical outcome. The suggestions of improvement in outcome must be confirmed in further studies.

The role of the critical event committee in a major cardiovascular outcome study.

Outcome studies in cardiovascular diseases such as hypertension are often based in a number of countries recruiting from multiple centres. This can lead to difficulties in end-point evaluation and classification. The INSIGHT study provided the unique opportunity to examine the role and usefulness of a Critical Event Committee (CEC) established to examine all events occurring in a cohort of 6321 patients and classifying them according to pre-determined criteria. More than 28% of investigator-coded primary events and more than 41% of secondary events were re-classified by the CEC. Particularly difficult diagnoses included myocardial infarction, angina and heart failure, and the database finally analysed was substantially altered after CEC Committee evaluation. Post hoc analysis of the INSIGHT database demonstrated that the primary events compared would have been reduced from 6.3% vs 5.8% of those randomized on nifedipine vs co-amilozide to 5.1% vs 4.7%--an overall reduction of 72 events of 382, a fall of 18.8%. We conclude that a CEC should be a crucial component of any large outcome study and that if all events are subjected to scrutiny, the quality of the database is greatly enhanced.