Transcranial Doppler sonography for detecting stenosis or occlusion of intracranial arteries in people with acute ischaemic stroke.

BACKGROUND: An occlusion or stenosis of intracranial large arteries can be detected in the acute phase of ischaemic stroke in about 42% of patients. The approved therapies for acute ischaemic stroke are thrombolysis with intravenous recombinant tissue plasminogen activator (rt-PA), and mechanical thrombectomy; both aim to recanalise an occluded intracranial artery. The reference standard for the diagnosis of intracranial stenosis and occlusion is intra-arterial angiography (IA) and, recently, computed tomography angiography (CTA) and magnetic resonance angiography (MRA), or contrast-enhanced MRA. Transcranial Doppler (TCD) and transcranial colour Doppler (TCCD) are useful, rapid, noninvasive tools for the assessment of intracranial large arteries pathology. Due to the current lack of consensus regarding the use of TCD and TCCD in clinical practice, we systematically reviewed the literature for studies assessing the diagnostic accuracy of these techniques compared with intra-arterial IA, CTA, and MRA for the detection of intracranial stenosis and occlusion in people presenting with symptoms of ischaemic stroke. OBJECTIVES: To assess the diagnostic accuracy of TCD and TCCD for detecting stenosis and occlusion of intracranial large arteries in people with acute ischaemic stroke. SEARCH METHODS: We limited our searches from January 1982 onwards as the transcranial Doppler technique was only introduced into clinical practice in the 1980s. We searched MEDLINE (Ovid) (from 1982 to 2018); Embase (Ovid) (from 1982 to 2018); Database of Abstracts of Reviews of Effects (DARE); and Health Technology Assessment Database (HTA) (from 1982 to 2018). Moreover, we perused the reference lists of all retrieved articles and of previously published relevant review articles, handsearched relevant conference proceedings, searched relevant websites, and contacted experts in the field. SELECTION CRITERIA: We included all studies comparing TCD or TCCD (index tests) with IA, CTA, MRA, or contrast-enhanced MRA (reference standards) in people with acute ischaemic stroke, where all participants underwent both the index test and the reference standard within 24 hours of symptom onset. We included prospective cohort studies and randomised studies of test comparisons. We also considered retrospective studies eligible for inclusion where the original population sample was recruited prospectively but the results were analysed retrospectively. DATA COLLECTION AND ANALYSIS: At least two review authors independently screened the titles and abstracts identified by the search strategies, applied the inclusion criteria, extracted data, assessed methodological quality (using QUADAS-2), and investigated heterogeneity. We contacted study authors for missing data. MAIN RESULTS: A comprehensive search of major relevant electronic databases (MEDLINE and Embase) from 1982 to 13 March 2018 yielded 13,534 articles, of which nine were deemed eligible for inclusion. The studies included a total of 493 participants. The mean age of included participants was 64.2 years (range 55.8 to 69.9 years). The proportion of men and women was similar across studies. Six studies recruited participants in Europe, one in south America, one in China, and one in Egypt. Risk of bias was high for participant selection but low for flow, timing, index and reference standard. The summary sensitivity and specificity estimates for TCD and TCCD were 95% (95% CI = 0.83 to 0.99) and 95% (95% CI = 0.90 to 0.98), respectively. Considering a prevalence of stenosis or occlusion of 42% (as reported in the literature), for every 1000 people who receive a TCD or TCCD test, stenosis or occlusion will be missed in 21 people (95% CI = 4 to 71) and 29 (95% CI = 12 to 58) will be wrongly diagnosed as harbouring an intracranial occlusion. However, there was substantial heterogeneity between studies, which was no longer evident when only occlusion of the MCA was considered, or when the analysis was limited to participants investigated within six hours. The performance of either TCD or TCCD in ruling in and ruling out a MCA occlusion was good. Limitations of this review were the small number of identified studies and the lack of data on the use of ultrasound contrast medium. AUTHORS' CONCLUSIONS: This review provides evidence that TCD or TCCD, administered by professionals with adequate experience and skills, can provide useful diagnostic information for detecting stenosis or occlusion of intracranial vessels in people with acute ischaemic stroke, or guide the request for more invasive vascular neuroimaging, especially where CT or MR-based vascular imaging are not immediately available. More studies are needed to confirm or refute the results of this review in a larger sample of stroke patients, to verify the role of contrast medium and to evaluate the clinical advantage of the use of ultrasound.

Prevalence of intracranial large artery stenosis and occlusion in patients with acute ischaemic stroke or TIA.

Intracranial large artery stenosis and occlusion disease has been considered to be the cause of 8­10 % of ischaemic strokes in North America, and 30­50 % of strokes and more than 50 % of transient ischaemic attacks in Chinese population. So far we do not know the real prevalence of intracranial disease (ID) and the distribution of its risk factors in European population. We aimed to determine the prevalence and risk factors of ID in a European stroke population with computed tomography angiography (CTA). A retrospective study of consecutive ischaemic patients at the Stroke Unit of Utrecht, The Netherlands, from September 2006 to August 2008 was conducted. We assessed the presence of occlusion and/or stenosis of intracranial Internal Carotid Artery (ICA) and Middle Cerebral Artery on post-contrast 30-mm reconstruction axial CTA images. We analyzed the proportion of patients with ID, and the association of ID with risk factors and stroke subtype. In 220 patients (187 with stroke, 33 with TIA; mean age was 65 years, 57.3 % were male), intracranial stenosis was found in 6.4 % (95 % CI 3.9­10.4), intracranial occlusion in 34.5 % (95 % CI 28.6­41.0), and both occlusion and stenosis in 2.3 % (95 % CI 1.0­5.2). Multivariate analysis showed that the variables independently associated with ID were: extracranial ICA atherosclerosis (OR, 24.64; 95 % CI 6.30­96.38) and stroke subtypes TACS­PACS (OR, 7.61; 95 % CI 3.31­17.49). In conclusion, prevalence of intracranial stenosis in our study may well be consistent with previous observations in European and non-European population. ID may have been an underestimated condition in ischaemic Caucasian population.

Fibroblast growth factor-2 levels are elevated in the cerebrospinal fluid of multiple sclerosis patients.

In recent years a role has been recognized for fibroblast growth factor (FGF)-2 in the pathogenesis of demyelination and the failure of remyelination in experimental models of multiple sclerosis (MS). FGF-2 levels were determined using a sensitive immunoassay in the cerebrospinal fluid (CSF) of 20 patients with clinically isolated syndrome (CIS), 40 patients with relapsing-remitting (R-R) MS, and 30 patients with secondary progressive (SP) MS, correlated with MRI measures. Control CSF samples were obtained from 20 subjects who underwent lumbar puncture for diagnostic purposes and for whom all instrumental and laboratory analyses excluded systemic and nervous system diseases. FGF-2 levels in the CSF of MS and CIS patients were significantly higher than controls (P<0.001 and P<0.05, respectively). The highest levels were detected in R-R MS patients during relapse and in SP MS patients with an increase of 1 point in EDSS scores in the last 6 months. A significant correlation was found in SP MS patients with lesional load (R=0.43, P<0.01) but not with parenchymal fractions as measures of brain atrophy. A slight increase in serum FGF-2 levels was also found in R-R MS patients during relapse with gadolinium enhancing lesions and in SP patients with disability progression. These findings support the implication of FGF-2 in the pathogenesis of MS and concur with recent reports of the involvement of FGF receptor signalling in the disruption of myelin production in differentiated oligodendrocytes and in the loss of adult oligodendrocytes and myelin in vivo due to FGF-2.

Expression of ionotropic glutamate receptor GLUR3 and effects of glutamate on MBP- and MOG-specific lymphocyte activation and chemotactic migration in multiple sclerosis patients.

The present study was aimed at confirming the presence of GluR3 on T lymphocytes and to assess the effect of glutamate on proliferative responses to myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) and chemotactic migration to CXCL12/stromal cell-derived factor-1, RANTES, and MIP-1alpha in 15 control subjects and 20 relapsing-remitting multiple sclerosis (MS) patients (10 in a stable clinical phase and 10 during relapse). T lymphocytes of control subjects and MS patients express both mRNA and protein of GluR3 receptors, as shown by RT-PCR and immunoblot analyses. An up-regulation was evident during relapse and in patients with neuroradiological evidence of disease activity. Glutamate and AMPA at concentrations of 10 nM to 10 muM were able to enhance T lymphocyte proliferation to MBP and MOG and the chemotactic migration of T cells both in controls and MS patients. In the latter group, significantly higher proliferation values in response to glutamate were found in patients assessed during relapse and in those with gadolinium (Gd)+ enhancing lesions on MRI. Glutamate concentrations above 10 muM appeared to be inhibitory on MBP and MOG-specific T-lymphocyte proliferation as well as chemotactic response in both patients and controls. Higher GluR3 expression and higher activating effect of glutamate on T cells of MS patients during relapses and with evidence of disease activity on MRI suggests the involvement of glutamate-mediated mechanisms in the T-cell detrimental effects. In MS patients, glutamate within physiological ranges in the cerebrospinal fluid and brain extracellular space might enhance myelin antigen-specific proliferation and chemotactic migration via activation of AMPA receptors, which can be relevant for myelin and neuronal damage in MS. Excess glutamate levels seem to induce an inhibitory effect on lymphocyte function, and therefore the detrimental effect of this excitatory amino acid in this case could be attributed to a direct toxicity on glial and neuronal cells.

Cost assessment of headache in childhood and adolescence: preliminary data.

Headache, and in particular migraine, is a common disturbance in childhood and adolescence. The disabling nature of headache, evident in the adult, together with its effects on family life and reduction in performance of scholastic activity, make it a disease with an elevated social economic impact. We present preliminary results of a prospective study conducted over 6 months on a population of headache sufferers in childhood and adolescence who referred to our Juvenile Neuropsychiatry Centre of the Hospital of Perugia. Our objective was to quantify the direct and indirect costs associated with juvenile headache.