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

  • Protocol
  • Diagnostic

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the diagnostic accuracy of TCD and TCCD for detecting stenosis and occlusion of intracranial large arteries in people with acute ischaemic stroke.

We will assess the accuracy of different thresholds of mean flow velocity or peak systolic velocity, or both, in the grading of intracranial artery stenosis.

Background

Ischaemic stroke is the third leading cause of death and the most common cause of permanent disability (Warlow 2003). An occlusion or stenosis of intracranial large arteries can be detected in the acute phase of stroke in about 66% (range 34% to 80%) of people and a stenosis in about 14% (range 11% to 17%) (Alexandrov 1999; Gerriets 2000; Kassem-Moussa 2002; Arnold 2004; Brunser 2009), and it is commonly associated with a worse prognosis (Smith 2006).

The only effective approved therapy is recombinant tissue plasminogen activator (rt-PA), a thrombolytic agent given intravenously. Therapeutic benefits are greater the earlier the therapy is administered (Wardlaw 2012).

Non-randomised studies suggest the benefit of thrombolytic therapy may be greater among people with, than without, intracranial artery stenosis or occlusion (Fiebach 2012). A recent systematic review has shown that sonothrombolysis can increase recanalisation in people with acute ischaemic stroke and intracranial occlusion of the middle cerebral artery, with a reduction of death and disability at follow-up (Ricci 2012).

In addition to a person's clinical status and the duration of stroke symptoms at presentation, neuroimaging findings play an important role in the decision process about new acute stroke therapies. Whilst the technology to identify an ischaemic penumbra (i.e. ischaemic tissue that is not yet irreversibly injured and hence has the potential to be saved by acute reperfusion therapy) is complex and not widely available, the detection of vessel occlusion or stenosis by ultrasound is a more practical strategy for selecting people who might benefit from acute treatments. Some experts maintain that treatment (administered either intravenously or intra-arterially) should be given to people with evidence of intracranial vessel occlusion (von Kummer 2010). Rapid detection of symptomatic intracranial occlusion or stenosis may, therefore, help to identity people who are more likely to benefit from treatment beyond the first few hours of onset. A correct diagnosis of intracranial stenosis or occlusion has the potential to influence the management in the early phase of stroke and thus to improve outcome.

Transcranial colour doppler (TCD) and transcranial colour-coded duplex (TCCD) are imaging techniques that can be used in the acute phase of stroke to detect the presence of intracranial pathology (stenosis or occlusion, or both).

Target condition being diagnosed

The target conditions are stenosis and occlusion of intracranial large arteries. For the purpose of this review, we define stenosis of an intracranial vessel as any reduction of the lumen of the vessel, while occlusion is any complete interruption of the blood flow. We will consider these two conditions separately, but we will analyse them together as intracranial pathology in our main analysis.

The traditional reference standard for the diagnosis of intracranial stenosis and occlusion is intra-arterial angiography, an invasive method that carries a 1% to 2% risk of stroke or death (Hankey 1990). Intra-arterial angiography involves the injection of iodine contrast agent after selective catheterisation of the vessels to the brain. X-ray images are taken before ('the mask') and during contrast injection. The mask is then subtracted from the post-contrast images. All that remains should be the blood vessels that were filled with contrast material.

Since the early 1990s, new less-invasive imaging methods, such as computer tomography angiography (CTA) and magnetic resonance angiography (MRA), or contrast-enhanced MRA, have been increasingly used in clinical practice to identify people with intracranial stenosis and occlusion. CT combines the use of x-rays with computerised analysis of the images. In CTA the injection of intravenous radio-opaque contrast agent accentuates blood vessels during the arterial phase of contrast perfusion. MR uses the electromagnetic properties of protons to produce high-quality cross-sectional images of the brain. MRA is a group of techniques based on MR imaging. They use intravenous contrast to highlight vessels (contrast-enhanced MRA) or take advantage of blood flow to distinguish the vessels from other static tissue (e.g. time-of-flight techniques).

In clinical practice, intra-arterial angiography has gradually been replaced by CTA and MRA, which have shown satisfactory accuracy in the detection of intracranial stenosis and occlusion (Latchaw 2009).

Index test(s)

TCD and TCCD are becoming increasingly popular in clinical practice. TCD uses frequencies of 1 to 2.5 MHz to insonate cerebral vessels through several windows in the skull (transtemporal, transforaminal and transorbital). This technique can detect intracranial flow velocities and the direction of flow measured by a pulsed doppler. TCCD uses frequencies of 1.5 to 4 MHz to obtain the same information, and add 'B-mode' and 'colour doppler' imaging that displays a two-dimensional image of cerebral vessels and parenchyma as seen by the ultrasound probe. Ultrasound contrast agent is used if the temporal acoustic bone window has insufficient signal intensity, or proximal branches of the circle of Willis are not visible.

Intracranial stenosis is detected as a colour and a pulsed-wave pattern of increased blood flow velocity. Occlusion is detected as the absence of a colour doppler signal and pulsed-wave spectrum on the index artery whilst any other artery is detectable from the same acoustic window. Some parameters can be used to quantify the stenosis grade: peak systolic velocity, which is defined as the highest velocity of the systolic wave within the doppler frequency spectrum, and mean flow velocity, which consists of an averaging of all instantaneous velocity values within a cardiac cycle.

TCD and TCCD are useful, rapid, non-invasive tools for the assessment of acute stroke. The equipment is portable and can, therefore, be used for bedside investigations, especially for those people who cannot tolerate conventional neuroimaging. They provide clinical results in a short period of time (minutes) and can be repeated over time, hence might have potential advantages in the evaluation and monitoring of people in the early phase of stroke. Furthermore, they are relatively inexpensive, and may be more accessible than neuroimaging and intra-arterial angiography in many city hospitals in many countries.

Clinical pathway

TCD and TCCD have the potential to improve the identification of people with stenosis or occlusion, or both. Therefore, they may be used to replace the more invasive, complex, and expensive imaging methods (i.e. intra-arterial angiography, CTA, MRA, and contrast-enhanced MRA) currently used in clinical practice.

If a person fulfils the criteria for thrombolysis this is performed irrespective of the results of TCD or TCCD. In people receiving thrombolytic therapy ultrasound evaluation can be used to inform the prognosis, to check whether the recanalisation occurs and, in a few cases, to decide whether to change to intra-arterial therapy.

When thrombolysis cannot be given, ultrasound examination can still be used for prognosis and monitoring. Trials on the therapeutic use of ultrasound are currently ongoing (e.g. sonothrombolysis for acute ischaemic stroke). Therefore, the diagnostic use of ultrasound is essential for the administration of specific treatments in stroke medicine.

Rationale

In people who present to the emergency department with symptoms of ischaemic stroke, the rapid and accurate identification of occlusion or stenosis of large intracranial arteries is important to establish proper management and improve clinical outcomes. The detection of a vascular occlusion, for example, allows selection of people with acute ischaemic stroke who might benefit from treatment with intravenous fibrinolytic therapy beyond six hours, intra-arterial thrombolysis or sonothrombolysis. Even though intra-arterial angiography, CTA, MRA, and contrast-enhanced MRA are considered the best available methods for the diagnosis of intracranial occlusion and stenosis, they are invasive, time-consuming, expensive and not available in many centres. Moreover, they are not tolerated by some people.

TCD and TCCD are often used prior to, or instead of, intra-arterial angiography, CTA, MRA, or contrast-enhanced MRA in people with ischaemic acute stroke. The Neurosonology in Acute Ischaemic Stroke (NAIS) study suggests that ultrasound techniques could be used to predict clinical outcomes at a very early stage, thereby allowing therapeutic interventions to be tailored to suit individuals' needs (Allendoerfer 2006). However, there is currently no formal consensus on the use of neurosonology in the management of the acute phase of stroke. The use of TCD and TCCD varies between countries. In the USA, TCD is considered useful in assessing people within eight hours of stroke onset, monitoring the effects of thrombolytic therapy over time, and establishing prognosis (Adams 2007). According to the ESO Guidelines 2008, TCD can contribute to the selection of people with stroke who might receive intra-arterial treatments in specialised centres. The Italian stroke guidelines indicate that in the acute phase of stroke, neurosonology of intracranial arteries may be a valid alternative to more invasive techniques (SPREAD 2013). At present, in the UK the assessment of intracranial vessels is not regarded as crucial for the management of acute stroke (NICE Guidelines 2008). Due to the current lack of consensus regarding the use of TCD and TCCD in clinical practice, we aim to review systematically the literature for studies assessing the diagnostic accuracy of these techniques compared with intra-arterial angiography, 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.

Secondary objectives

We will assess the accuracy of different thresholds of mean flow velocity or peak systolic velocity, or both, in the grading of intracranial artery stenosis.

Methods

Criteria for considering studies for this review

Types of studies

We will include all studies comparing TCD or TCCD with intra-arterial angiography, CTA, MRA, or contrast-enhanced MRA in people with acute ischaemic stroke where all participants undergo both the index test and the reference standard within 24 hours of symptom onset. We will include prospective cohort studies (single gate) and randomised controlled studies in which participants are randomised to TCD or TCCD and compared with the reference standards. We will also consider as eligible for inclusion retrospective studies where the original population sample was recruited prospectively but the results were analysed retrospectively.

Participants

Adults (as defined by the studies' investigators) presenting in emergency departments or specialist units (i.e. stroke units, neurological departments) with acute ischaemic stroke confirmed by imaging (CT or MR). We will include people irrespective of the severity of their disease as long as they were stable enough to undergo the tests under investigation.

Index tests

We will assess the following index tests:

  • TCD - with or without echo contrast agents - performed with a low frequency probe device (1.0 to 2.5 MHz);

  • TCCD - with or without echo contrast agents - performed with a low frequency probe device (1.5 to 4.0 MHz).

We will accept the definition of stenosis as reported by the individual papers (i.e. peak systolic velocity criteria or mean flow velocity criteria, or both).

Target conditions

Stenosis or occlusion of intracranial large arteries resulting in acute ischaemic stroke.

Reference standards

We will consider the following as a suitable reference standard:

  • intra-arterial angiography; or

  • CTA; or

  • MRA (time-of-flight technique or contrast-enhanced MRA).

We will consider the above imaging tests interchangeable.

Search methods for identification of studies

We will perform a comprehensive literature search with no language restriction to identify relevant studies for this review. We will limit our searches from January 1982 onwards as the transcranial doppler technique was only introduced into clinical practice in the 1980s.

Electronic searches

We will search the following electronic bibliographic databases:

We will use a combination of controlled vocabulary and relevant free text terms for each database. Although stenosis of the intracranial internal carotid artery is relevant for this review we will not include controlled vocabulary and free text terms to describe the general concept of 'carotid stenosis' in the search strategies. This is justified as the focus of this review is specifically on the stenosis or occlusion of intracranial arteries and not on carotid stenosis of the neck arteries. Inclusion of terms relating to 'carotid stenosis' and 'carotid artery disease' will retrieve an unmanageable number of irrelevant citations. We have developed the MEDLINE and EMBASE search strategies in collaboration with the Cochrane Stroke Group Trials Search Co-ordinator (Brenda Thomas) following the recommendations of the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy (de Vet 2008). Both search strategies have been constructed in a very complex way using a number of perfectly reasonable combinations of concepts. Both strategies also include a methodological search filter for studies of diagnostic accuracy. The use of a search filter, even though it may reduce the overall sensitivity of the literature searches, is justified by the fact that a literature search combining MeSH terms and text words for the target condition with those for the imaging tests under evaluation (as for the current recommendation of the Screening and Diagnostic Tests Methods Group) would retrieve a number of citations that would be unmanageable within the timeline for the completion of this review. Furthermore, the methodological filter is based on the diagnostic component of the search strategy developed and validated by Astin and colleagues to identify diagnostic accuracy studies on imaging (Astin 2008). We have adapted the MEDLINE search strategy to search the other electronic databases.

Searching other resources

In an effort to identify further published, unpublished and ongoing studies we will:

  1. scan the reference lists of all relevant articles obtained and previously published review articles on the subject;

  2. handsearch relevant conference proceedings;

  3. contact experts in the field;

  4. search the following relevant web sites using the terms 'intracranial stenosis'; 'intracranial occlusion'; 'stroke'; 'transcranial doppler':

    1. National Institute of Neurological Diseases and Stroke NINDS (www.ninds.nih.gov);

    2. American Heart Association AHA (http://www.heart.org/HEARTORG/);

    3. American Stroke Association - ASA (http://www.strokeassociation.org/STROKEORG/);

    4. National Stroke Association - NSA (www.stroke.org);

    5. Scottish Intercollegiate Guidelines Network - SIGN (www.sign.ac.uk);

    6. MEDION (www.mediondatabase.nl);

    7. ClinicalTrials.gov (www.clinicaltrials.gov);

    8. Google Scholar (http://scholar.google.co.uk/);

  5. use Science Citation Index Cited Reference Search for forward tracking of important articles.

We will import the citations identified by the search strategies into Reference Manager bibliographic database (Reference Manager 10).

Data collection and analysis

Selection of studies

At least two review authors will independently screen the titles and abstracts of all records generated by the electronic searches for relevance. We will exclude duplicates and studies that did not meet the inclusion criteria. We will retrieve copies of all remaining potentially relevant reports in full. At least two review authors will independently assess the full text reports for inclusion using a study eligibility screening form based on the pre-specified inclusion criteria. We will refer any disagreement that cannot be resolved by discussion to a third review author.

We will only evaluate reports published in full. For studies presented as conference proceedings, we will attempt to identify an existing full-text publication. For studies published in multiple reports, we will only include the latest or most relevant report. We will consider studies suitable for inclusion if the absolute numbers of true positives, false positives, false negatives, and true negatives observations are available or can be derived from the data reported in the primary studies.

Data extraction and management

We will design a data abstraction form to record details from included studies. At least two review authors will independently extract the following information from each individual study (without concealing the study authorship or other publication details).

  • Bibliographic details of included studies: author, title, year of publication, journal.

  • Study design: method of recruitment, sampling procedures, geographical location.

  • Clinical and demographic characteristics of participants: number of participants, age, gender, setting, severity of stroke, stroke clinical syndrome (i.e. anterior, posterior), concomitant diseases, inclusion and exclusion criteria.

  • Details of the index tests: technical characteristics of TCD and TCCD, criteria used for defining stenosis and occlusion, timing of test, expertise of the clinician or technician performing the procedure, location of stenosis or occlusion, adverse events and patient acceptability.

  • Details of the reference standards: type of reference standards (intra-arterial angiography, CTA, MRA, or contrast-enhanced MRA), timing, location of stenosis or occlusion.

  • Numerical results: data for 2 x 2 tables (true positives, true negatives, false positives, and false negatives).

The review authors will resolve any disagreements by discussion or arbitration. We will enter 'consensus' data in a separate printed or electronic form. We will try to contact study authors for missing data.

Assessment of methodological quality

At least two review authors will independently assess the methodological quality of each included study using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2), a recent modified version of QUADAS (Whiting 2011). QUADAS is a checklist for assessment of the methodological quality of studies included in systematic reviews of diagnostic accuracy, and was developed by the NHS Centre for Reviews and Dissemination at the University of York, UK. The QUADAS-2 comprises four domains: (1) participant selection, (2) index test, (3) reference standard, and (4) flow of participants through the study and timing of the index tests and reference standard (flow and timing). Each domain is assessed for risk of bias, and the first three domains are also assessed for concerns regarding applicability. Risk of bias and concerns about applicability are judged as 'low', 'high' or 'unclear'. We will add signalling questions, specific to this review topic, separately.

We will consider an appropriate spectrum of participants presenting with acute ischaemic stroke symptoms evaluated within 24 hours of symptoms onset. With regard to the time interval between index test and reference standard we will accept any time interval reported by the study investigators, providing that both tests (index and reference standard) are performed within 24 hours of symptoms onset (i.e. on day 1).

The modified QUADAS-2 checklist is shown in Table 1 and in Appendix 3. We will resolve any disagreements by discussion or arbitration. For each individual study we will tabulate the agreed results of the quality assessment. We will also present the results of the methodological quality assessment graphically.

Table 1. Risk of bias and applicability judgements for the quality assessment of diagnostic accuracy studies (QUADAS-2)
Domain Patient selection Index test Reference standard Flow and timing
DescriptionDescribe methods of patient
selection
Describe included patients (previous testing, presentation, intended use of index
test, and setting)
Describe the index test and how it was conducted
and interpreted
Describe the reference standard and how it was conducted and interpretedDescribe any patients who did not receive the index tests or reference standard or who were excluded from the 2 x 2 table (refer to flow diagram)
Describe the interval and any interventions between index tests and the reference standard
Signalling question (yes, no, or unclear)Was a consecutive or random sample of patients enrolled?
Was a case-control design avoided?
Did the study avoid inappropriate exclusions?
Were the index test results interpreted without knowledge of the results of the reference standard? If a threshold was used, was it prespecified?Is the reference standard likely to correctly classify the target condition?
Were the reference standard results interpreted without knowledge of the results of the index test?
Was there an appropriate interval between index
tests and reference standard?
Did all patients receive a reference standard?
Did all patients receive the same reference standard?
Were all patients included in the analysis?
Risk of bias (high, low, or unclear)Could the selection of patients have introduced bias?Could the conduct or interpretation of the index test have introduced bias?Could the reference standard, its conduct, or its interpretation have introduced bias?Could the patient flow have introduced bias?
Concerns about applicability (high, low, or unclear)Are there concerns that the included patients do not match the review question?Are there concerns that the index test, its conduct, or its interpretation differ from the review question?Are there concerns that the target condition as defined by the reference standard does not match the review question? 

Statistical analysis and data synthesis

We will extract or derive indices of diagnostic performance from data presented in each primary study for each test and we will generate 2 X 2 contingency tables of true positive cases, false positive cases, false negative cases, and true negative cases. We will calculate sensitivity and specificity with 95% confidence intervals (CI) for each test in each study. We will use forest plots to display the sensitivity and specificity estimates measured in each study and to illustrate the variation in estimates between studies.

We will plot the results of studies for individual diagnostic tests in a receiver operator characteristic (ROC) space.

We will meta-analyse the pairs of sensitivities and specificities. The primary analysis will aim at comparing TCD and TCCD versus CTA, MRA, contrast-enhanced MRA or intra-arterial angiography. We will also investigate the performance of each index test versus each reference test. We will use the Hierarchical Summary ROC Curve (HSROC) proposed by Rutter and Gatsonis (Rutter 2001) to model the threshold effects. We intend to use the SAS program PROC NLMIXED for generating the HSROC model (Macaskill 2004) (SAS version 9.1 for Windows; SAS Institute Inc, USA). We will accept the definition of stenosis given in any individual study. In general, we will consider mean flow velocity thresholds ranging from ≥ 80 cm/s to ≥ 120 cm/s and ≥ 120 cm/s to ≥ 230 cm/s. We will also take TCD thresholds (from 1.0 to 2.5 MHz) and TCD thresholds (from 1.5 to 4.0 MHz) into account.

Initially we will analyse stenosis and occlusion together as one condition and subsequently (where possible) we will perform separate analyses for stenosis and for occlusion.

Investigations of heterogeneity

Where possible, we will formally investigate heterogeneity by adding covariates for each source of heterogeneity to the HSROC model.

We will also investigate the performance of each index test versus each reference test.

We intend to add covariates related to:

  • type of reference standard (CTA, MRA, contrast-enhanced MRA, or intra-arterial angiography);

  • clinical criteria for occlusion/stenosis (i.e. mean flow velocity and peak systolic velocity);

  • time between index test and reference standard;

  • operator expertise (defined according to the study methods);

  • stroke severity (defined by the National Institutes of Health Stroke Scale (NIHSS) or any other scale used in the study).

 

Sensitivity analyses

We intend to conduct sensitivity analyses with respect to the following types of studies:

  • studies assessing participants within 12 hours of onset of stroke symptoms;

  • M-mode for TCD;

  • Power Doppler/B-flow for TCCD;

  • studies not fulfilling QUADAS item 2.

Assessment of reporting bias

We will not investigate reporting bias as the methods for addressing publication bias in systematic reviews of diagnostic test accuracy are not yet well developed.

Acknowledgements

We thank Brenda Thomas for her assistance with the literature searches.

Appendices

Appendix 1. MEDLINE (Ovid) search strategy – January 1982 onwards

1. cerebrovascular disorders/ or basal ganglia cerebrovascular disease/ or brain ischemia/ or brain infarction/ or exp brain stem infarctions/ or cerebral infarction/ or infarction, anterior cerebral artery/ or infarction, middle cerebral artery/ or infarction, posterior cerebral artery/ or hypoxia-ischemia, brain/ or intracranial arterial diseases/ or cerebral arterial diseases/ or Intracranial Arteriosclerosis/ or exp "intracranial embolism and thrombosis"/ or stroke/
2. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or hypoxi$)).tw.
3. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva)).tw.
4. ((intracranial or intra-cranial or brain arter$ or cerebral arter$ or basilar arter$ or vertebral art$ or intracerebral or intra-cerebral) adj5 (stenosis or stenoses or steno-occlu$ or occlusion or occluded or occlusive or narrow$ or arteriosclero$ or atherosclero$ or plaque or plaques)).tw.
5. basilar artery/ or exp cerebral arteries/ or vertebral artery/
6. Constriction, Pathologic/ or arterial occlusive diseases/ or arteriosclerosis/ or (stenosis or stenoses or steno-occlu$ or occlusion or occluded or occlusive or narrow$ or arteriosclero$ or atherosclero$ or plaque or plaques).tw.
7. 5 and 6
8. 1 or 2 or 3 or 4 or 7
9. ultrasonography, doppler, transcranial/ or ultrasonography, doppler/ or ultrasonography, doppler, duplex/ or ultrasonography, doppler, color/ or ultrasonography, doppler, pulsed/ or echoencephalography/
10. ultrasonography/ and blood flow velocity/
11. ((transcranial or duplex or color or colour) adj5 doppler).tw.
12. (TCD or TCCD).tw.
13. ((doppler or duplex) adj5 (sonogra$ or ultrasonogra$)).tw.
14. Transcranial Color-Coded Duplex.tw.
15. 9 or 10 or 11 or 12 or 13 or 14
16. Magnetic Resonance Angiography/
17. angiography/ or cerebral angiography/
18. Magnetic Resonance Imaging/
19. 17 and 18
20. ((magnetic resonance or MR or MRI or NMR) adj5 (angiogra$ or arteriogra$)).tw.
21. MRA.tw.
22. exp Tomography, X-Ray Computed/
23. angiography/ or cerebral angiography/
24. 22 and 23
25. ((Compute$ tomograph$ or CT or CAT) adj5 (angiogra$ or arteriogra$)).tw.
26. CTA.tw.
27. angiography, digital subtraction/
28. angiography/ and (subtraction technique/ or subtraction.tw.)
29. ((digital subtract$ or catheter or cerebral or brain or intra-arterial) adj5 (angiogra$ or arteriogra$)).tw.
30. (DSA or IADSA).tw.
31. 16 or 19 or 20 or 21 or 24 or 25 or 26 or 27 or 28 or 29 or 30
32. *cerebrovascular disorders/di, pa, ra, us or *basal ganglia cerebrovascular disease/di, pa, ra, us or *brain ischemia/di, pa, ra, us or *brain infarction/di, pa, ra, us or exp *brain stem infarctions/di, pa, ra, us or *cerebral infarction/di, pa, ra, us or *infarction, anterior cerebral artery/di, pa, ra, us or *infarction, middle cerebral artery/di, pa, ra, us or *infarction, posterior cerebral artery/di, pa, ra, us or *hypoxia-ischemia, brain/di, pa, ra, us or *intracranial arterial diseases/di, pa, ra, us or *cerebral arterial diseases/di, pa, ra, us or *Intracranial Arteriosclerosis/di, pa, ra, us or exp *"intracranial embolism and thrombosis"/di, pa, ra, us or *stroke/di, pa, ra, us
33. *basilar artery/us or exp *cerebral arteries/us or *vertebral artery/us
34. 32 or 33
35. exp "sensitivity and specificity"/
36. (sensitiv$ or specificity).tw.
37. (predictive adj5 value$).tw.
38. exp diagnostic errors/
39. ((false adj positive$) or (false adj negative$)).tw.
40. (observer adj variation$).tw.
41. (roc adj curve).tw.
42. (likelihood adj3 ratio$).tw.
43. likelihood function/
44. 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43
45. cerebrovascular disorders/us or basal ganglia cerebrovascular disease/us or brain ischemia/us or brain infarction/us or exp brain stem infarctions/us or cerebral infarction/us or infarction, anterior cerebral artery/us or infarction, middle cerebral artery/us or infarction, posterior cerebral artery/us or hypoxia-ischemia, brain/us or intracranial arterial diseases/us or cerebral arterial diseases/us or Intracranial Arteriosclerosis/us or exp "intracranial embolism and thrombosis"/us or stroke/us
46. 33 or 45
47. 8 and 15 and 31
48. 15 and 34
49. 8 and 15 and 44
50. 44 and 46
51. 47 or 48 or 49 or 50
52. (1982$ or 1983$ or 1984$ or 1985$ or 1986$ or 1987$ or 1988$ or 1989$ or 199$ or 20$).ed.
53. 51 and 52

Appendix 2. EMBASE (Ovid) search strategy – January 1982 onwards

1. cerebrovascular disease/ or cerebral artery disease/ or cerebrovascular accident/ or stroke/ or vertebrobasilar insufficiency/ or exp brain infarction/ or exp brain ischemia/ or exp occlusive cerebrovascular disease/ or brain atherosclerosis/
2. stroke patient/ or stroke unit/
3. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or hypoxi$)).tw.
4. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva)).tw.
5. ((intracranial or intra-cranial or brain arter$ or cerebral arter$ or basilar arter$ or vertebral art$ or intracerebral or intra-cerebral) adj5 (stenosis or stenoses or steno-occlu$ or occlusion or occluded or occlusive or narrow$ or arteriosclero$ or atherosclero$ or plaque or plaques)).tw.
6. exp brain artery/ or vertebral artery/
7. "stenosis, occlusion and obstruction"/ or stenosis/ or occlusion/ or blood vessel occlusion/ or artery occlusion/ or obstruction/ or arteriosclerosis/ or artery thrombosis/ or atherosclerotic plaque/ or atherosclerosis/ or artery intima proliferation/
8. (stenosis or stenoses or steno-occlu$ or occlusion or occluded or occlusive or narrow$ or arteriosclero$ or atherosclero$ or plaque or plaques).tw.
9. 7 or 8
10. 6 and 9
11. 1 or 2 or 3 or 4 or 5 or 10
12. echography/ or doppler echography/ or real time echography/ or color ultrasound flowmetry/
13. echography/ and blood flow velocity/
14. ((transcranial or duplex or color or colour) adj5 doppler).tw.
15. (TCD or TCCD).tw.
16. ((doppler or duplex) adj5 (sonogra$ or ultrasonogra$)).tw.
17. Transcranial Color-Coded Duplex.tw.
18. 12 or 13 or 14 or 15 or 16 or 17
19. magnetic resonance angiography/
20. angiography/ or arteriography/ or exp brain angiography/
21. nuclear magnetic resonance imaging/
22. 20 and 21
23. ((magnetic resonance or MR or MRI or NMR) adj5 (angiogra$ or arteriogra$)).tw.
24. MRA.tw.
25. computed tomographic angiography/
26. angiography/ or arteriography/ or exp brain angiography/
27. computer assisted tomography/ or spiral computer assisted tomography/
28. 26 and 27
29. ((compute$ tomograph$ or CT or CAT) adj5 (angiogra$ or arteriogra$)).tw.
30. CTA.tw.
31. conventional angiography/ or digital subtraction angiography/
32. image subtraction/ or subtraction.tw.
33. angiography/ or arteriography/ or exp brain angiography/
34. 32 and 33
35. ((digital subtract$ or catheter or cerebral or brain) adj5 (angiogra$ or arteriogra$)).tw.
36. (DSA or IADSA).tw.
37. 19 or 22 or 23 or 24 or 25 or 28 or 29 or 30 or 31 or 34 or 35 or 36
38. *cerebrovascular disease/di or *cerebral artery disease/di or *cerebrovascular accident/di or *stroke/di or *vertebrobasilar insufficiency/di or exp *brain infarction/di or exp *brain ischemia/di or exp *occlusive cerebrovascular disease/di or *brain atherosclerosis/di
39. "sensitivity and specificity"/
40. receiver operating characteristic/
41. diagnostic accuracy/
42. exp diagnostic error/
43. observer variation/
44. "limit of detection"/
45. "diagnostic test accuracy study".sh.
46. (sensitivity or specificity).tw.
47. (predictive adj3 value$).tw.
48. ((false adj positive$) or (false adj negative$)).tw.
49. observer variation$.tw.
50. (roc adj curve$).tw.
51. (likelihood adj3 ratio$).tw.
52. or/39-51
53. 11 and 18 and 37
54. 18 and 38
55. 11 and 18 and 52
56. 53 or 54 or 55
57. (1982$ or 1983$ or 1984$ or 1985$ or 1986$ or 1987$ or 1988$ or 1989$ or 199$ or 20$).em.
58. 56 and 57
59. (animal/ or nonhuman/ or animal experiment/) and human/
60. animal/ or nonhuman/ or animal experiment/
61. 60 not 59
62. 58 not 61

Appendix 3. QUADAS tool

Domain 1 - Patient selection

1.1 Was a consecutive or random sample of patients enrolled?
  • Yes is scored when either a consecutive or random sample of patients with acute ischaemic stroke was enrolled.

  • No is scored when a consecutive or random sample of patients with acute ischaemic stroke was not enrolled.

  • Unclear is scored when there is insufficient information to make a decision.

1.2 Was a case-control design avoided?
  • Yes is scored when a case-control design is avoided.

  • No is scored when a case-control design is not avoided.

  • Unclear is scored when there is insufficient information to make a decision.

1.3 Did the study avoid inappropriate exclusions?
  • Yes is scored when inappropriate exclusions were avoided (i.e. all patients assessed with TCD/TCCD against either CTA, MRA, contrast-enhanced MRA or IA angiography are considered).

  • No is scored when inappropriate exclusions were not avoided (e.g. patients with test findings ‘difficult’ to interpret or patients with severe stroke symptoms are not considered).

  • Unclear is scored when there is insufficient information to make a decision.

Domain 2 – Index test

2.1 Were the index test results interpreted without knowledge of the results of the reference standard?
  • Yes is scored when results of the TCD/TCCD are interpreted without knowledge of the results of either CTA, MRA, contrast-enhanced MRA or IA angiography.

  • No is scored when results of the TCD/TCCD are interpreted knowing already the results of either CTA, MRA, contrast-enhanced MRA or IA angiography.

  • Unclear is scored when there is insufficient information on the way TCD/TCCD and the reference tests were interpreted.

2.2 If a threshold was used, was it prespecified?
  • Yes is scored when a TCD/TCCD threshold was prespecified (e.g. MFV thresholds ranging from ≥ 80 cm/s to ≥ 120 cm/s and ≥ 120 cm/s to ≥ 230 cm/s).

  • No is scored when a TCD/TCCD threshold was not prespecified.

  • Unclear is scored when there is insufficient information to make a decision.

Domain 3 – Reference standard

3.1 Is the reference standard likely to correctly classify the target condition?
  • Yes is scored when the reference standard used is either CTA, MRA or contrast-enhanced MRA, or IA angiography.

  • No is scored when another test, different from IA angiography, CTA, MRA or contrast-enhanced MRA, is used as reference standard.

  • Unclear is scored when there is insufficient information on the reference standard used.

3.2 Were the reference standard results interpreted without knowledge of the results of the index test?
  • Yes is scored when results of the reference tests are interpreted without knowledge of the TCD/TCCD findings in cases when reference tests are used before the index standard.

  • No is scored when results of the reference tests are interpreted knowing already the findings of the TCD/TCCD in cases when index tests are used before the reference tests.

  • Unclear is scored when there is insufficient information on the way TCD/TCCD and reference tests were interpreted.

Domain 4 – Flow and timing

4.1 Was there an appropriate interval between index tests and reference standard?
  • Yes is scored when intracranial arteries are examined by both the reference standard and the index tests within 24 hours.

  • No is scored when the time period between index tests and reference standard is more than 24 hours.

  • Unclear is scored when there is insufficient information on the time interval between tests.

4.2 Did all patients receive a reference standard?
  • Yes is scored when the whole sample of acute stroke patients or a random selection of the sample or a selection of the sample with consecutive series receive verification using either CTA, MRA, contrast-enhanced MRA or IA angiography.

  • No is scored when a part of the sample of acute stroke patients that is non-randomly or non-consecutively selected receives verification with either CTA, MRA, contrast-enhanced MRA or IA angiography.

  • Unclear is scored when there is insufficient information to ascertain if the whole sample or a random selection of the sample received verification with the reference standard.

4.3 Did all patients receive the same reference standard?
  • Yes is scored when study participants are tested with the same reference standard (either CTA, MRA, contrast-enhanced MRA or IA angiography) regardless of TCD/TCCD results.

  • No is scored when choice of the reference standard test is based on the TCD/TCCD results.

  • Unclear is scored when there is insufficient information on the different reference standard tests used.

4.4 Were all patients included in the analysis?
  • Yes is scored when all acute stroke patients were included in the analysis.

  • No is scored when all acute stroke patients were not included in the analysis.

  • Unclear is scored when there is insufficient information to make a decision.

Contributions of authors

AM, SR and SC conceived and designed the review. AM and MB developed the search strategies with additional input from Brenda Thomas, Trials Search Co-ordinator of the Cochrane Stroke Group. AM and MB designed the data extraction form. AM drafted the initial version of the protocol with additional input from MB, PS, SR. All authors have seen, commented on and approved the protocol.

Declarations of interest

Authors have no disclosures to report.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • European Federation Neurological Society grant, Italy.

Ancillary