What is the most sensitive non-invasive imaging strategy for the diagnosis of intracranial aneurysms?

OBJECTIVES: To determine whether combining non-invasive tests for intracranial aneurysms together would significantly improve aneurysm detection over individual tests. METHODS: 114 patients undergoing intra-arterial digital subtraction angiography to confirm or exclude an intracranial aneurysm were also examined by CT angiography, MR angiography, and transcranial power Doppler ultrasound. The reviewers and ultrasonographers were blinded to the angiogram result, other imaging results and all clinical information. RESULTS: The combination of non-invasive tests did improve diagnostic performance on a per patient basis. The combination of power Doppler and CT angiography had the greatest sensitivity for aneurysm detection (0.83; 05% confidence interval (95% CI) 0.66-0.93) and the level of agreement for this strategy with the reference angiographic standard was excellent (kappa 0.84; 95% CI 0.72-0.95). The improvement in sensitivity of adding power Doppler to CT angiography was not significant (p=0.55) but the improvement in the level of agreement with the reference standard was substantial. However, even the most sensitive combination strategy performed poorly in the detection of small (3-5 mm) and very small (<3 mm) aneurysms with a sensitivity of 0.43 (95% CI 0.23-0.66) and 0.00 (95% CI 0.00-0.31) respectively. CONCLUSIONS: The addition of transcranial power Doppler ultrasound to either CT angiography or MR angiography does improve diagnostic performance on a per patient basis but aneurysms of 5 mm or smaller can still not be reliably identified by current standard clinical non-invasive imaging modalities.     

Fluency in multiple sclerosis: which measure is best?

Tests of verbal fluency provide brief and sensitive measures of the deficits in rapidly retrieving overlearned information common in multiple sclerosis (MS). Production of words that begin with the letters F, A, and S is the verbal fluency measure most often used with patients who are fluent in English. However, because of frequency of words beginning with certain letters varies from one language to another, it is unlikely that any fixed set of letters will be appropriate for multicenter trials that involve patients who are fluent in different languages. A possible alternative involves using semantic fluency categories that contain such a large number of exemplars that no fluent speaker of any language could exhaust the category in the allotted response time. To examine the potential usefulness of semantic fluency measures, 203 MS patients and 87 healthy controls generated words that begin with F, A, or S or were exemplars of the categories animals and parts of the body. Receiver operating characteristic (ROC) curve analyses indicated that sensitivities and specificities for the three fluency measures in discriminating patients from controls were quite similar, especially if patients with global cognitive impairment were excluded.     

Anticoagulants, aspirin and dipyridamole in the secondary prevention of cerebral ischaemia: which is the best for which patient?

In this paper, an overview is given of trials with oral anticoagulants and dipyridamole in the secondary prevention after transient ischaemic attack or minor stroke. In patients with atrial fibrillation, the secondary preventive treatment of first choice is oral anticoagulation with an aimed international normalised ratio between 2.0 and 3.0. In patients without a cardiac source of embolism, a combination therapy of low-dose aspirin and dipyridamole 200 mg twice daily is the treatment of choice. These treatment strategies do however not prevent all recurrent strokes or vascular complications, and research for more effective strategies is warranted.     

Choice of endpoints in antiplatelet trials: which outcomes are most relevant to stroke patients?

The relative efficacies of different antiplatelet agents for stroke prevention are unclear because of differences in clinical trial design, a lack of direct comparisons between individual agents, and differences in the choice of primary endpoints. Individual endpoints in a clinical trial are often combined into a single primary endpoint cluster. Theoretically, a combined endpoint may reduce the sample size required to demonstrate significant benefits of an effective therapy. However, unless all components of a composite endpoint are affected in the same direction and to a similar degree, their inclusion may not provide the anticipated increase in statistical power. In fact, the use of a combined endpoint may lead to an underestimate of therapeutic benefits when patients at high risk for one particular endpoint are studied. For patients with stroke or TIA, the single outcome of stroke is particularly important because these patients have a higher risk of recurrent stroke than any other vascular outcome during the initial years after a stroke. Because of the low incidence of myocardial infarction (MI) in stroke trials, the inclusion of MI in the primary endpoint will usually have minimal influence on trial outcome, and antiplatelet therapy has not been shown to be beneficial in preventing nonvascular death. Chance variations in the incidence of MI or death may detract from the benefit of the agent for stroke prevention when it is included in a combined endpoint. The benefit of antiplatelet therapies for patients with recent cerebrovascular events is determined most accurately if stroke alone is chosen as the primary endpoint.     

Treatment in a combined acute and rehabilitation stroke unit: which aspects are most important?

BACKGROUND AND PURPOSE: We have previously shown that treatment of acute stroke patients in our stroke unit (SU) compared with treatment in general ward (GWs) improves short- and long-term survival and functional outcome and increases the possibility of earlier discharge to home. The aim of the present study was to identify the differences in treatment between the SU and the GW and to assess which aspects of the SU care which were most responsible for the better outcome. METHODS: Of the 220 patients included in our trial, only 206 were actually treated (SU, 102 patients; GW, 104 patients). For these patients, we identified the differences in the treatment and the consequences of the treatment. We analyzed the factors that we were able to measure and their association with the outcome, discharge to home within 6 weeks. RESULTS: Characteristic features in our SU were teamwork, staff education, functional training, and integrated physiotherapy and nursing. Other treatment factors significantly different in the SU from the GW were shorter time to start of the systematic mobilization/training and increased use of oxygen, heparin, intravenous saline solutions, and antipyretics. Consequences of the treatment seem to be less variation in diastolic and systolic blood pressure (BP), avoiding the lowest diastolic BP, and lowering the levels of glucose and temperature in the SU group compared with the GW group. Univariate analyses showed that all these factors except the level of glucose were significantly associated with discharge to home within 6 weeks. In the final multivariate Cox regression model, shorter time to start of the mobilization/training and stabilized diastolic BP were independent factors significantly associated with discharge to home within 6 weeks. CONCLUSIONS: Shorter time to start of mobilization/training was the most important factor associated with discharge to home, followed by stabilized diastolic BP, indicating that these factors probably were important in the SU treatment. The effects of characteristic features of an SU, such as a specially trained staff, teamwork, and involvement of relatives, were not possible to measure. Such factors might be more important than those actually measured.     

Quantitative functional measures in MS: what is a reliable change?

As a first step toward understanding which changes should be considered as meaningful, the authors assessed the reliability of quantitative functional tests on 5 consecutive days in 63 patients with MS, determining the range of measurement variability present when patients are clinically stable. Time to walk 25 feet (T25FW) and the 9-hole peg test (9HPT) varied by <20% of individual mean scores on repeated testing. Therefore, a 20% change on these tests can be considered to be the threshold that reliably indicates a true change in function for an individual.     

Role of calcium in neuronal cell injury: which subcellular compartment is involved?

It is widely believed that calcium plays a primary role in the development of neuronal cell injury in different pathological states of the brain. Disturbances of calcium homeostasis may be induced in three different subcellular compartments, the cytoplasm, mitochondria or the endoplasmic reticulum (ER). The traditional calcium hypothesis holds that neuronal cell injury is induced by a marked increase in cytoplasmic calcium activity during stress (e.g., cerebral ischemia). Recently, this hypothesis has been modified, taking into account that under different experimental conditions the extent of cell injury does not correlate closely with calcium load or total calcium influx into the cell, and that neuronal cell injury has been found to be associated with both increases and decreases of cytoplasmic calcium activity. The mitochondrial calcium hypothesis is based on the observation that after a severe form of stress there is a massive influx of calcium ions into mitochondria, which may lead to production of free radicals, opening of the mitochondrial permeability transition (MPT) pore and disturbances of energy metabolism. However, it has still to be established whether drugs such as cyclosporin A are neuroprotective through their effect on MPT or through the blocking of processes upstream of MPT. The ER calcium hypothesis arose from the observation that ER calcium stores are depleted after severe forms of stress, and that the response of cells to disturbances of ER calcium homeostasis (activation of the expression of genes coding for ER resident stress proteins and suppression of the initiation of protein synthesis) resembles their response to a severe form of stress (e.g., transient ischemia) implying common underlying mechanisms. Elucidating the exact mechanisms of calcium toxicity and identifying the subcellular compartment playing the most important role in this pathological process will help to evaluate strategies for specific therapeutic intervention.