Early recognition and initiation of reperfusion treatment is associated with more favourable outcome . However, the diagnostic accuracy of currently available tools does not allow reliable selection of patients who would benefit from a direct transfer to regional endovascular centres for mechanical thrombectomy, potentially leading to inappropriate and costly transfers .
Previous research has demonstrated sensitivity of TCD ultrasound ranging from 68% to 100% and specificity 78% to 99% for detecting acute vessel occlusion and stenosis [20–22,30,33–35]. It is a simple, non-invasive and affordable diagnostic tool that takes <15 minutes for a complete assessment of cerebral vessels [27,36] and can be performed in space-restricted environments, such as ambulances [16,37]. As demonstrated previously [16,38,39], transcranial grey-scale/TCD ultrasound images can be transferred from remotely supported ambulances in remote and rural areas for hospital-based expert interpretation, which reduces the requirement for skill acquisition and maintenance on the part of the on-scene assessor.
In the current exploratory study, we propose that the designed novel treatment decision tool based on transcranial grey-scale/TCD ultrasound together with clinical assessment findings could potentially improve the selection of patients with acute ischaemic stroke who would benefit from early initiation of reperfusion therapy, though further confirmatory work is required. It was demonstrated that the presence of cortical signs was significantly associated with the diagnosis of a stroke in general, and ischaemic stroke in particular. In agreement with previously published data, higher NIHSS total score [11,12], presence of cortical signs  and atrial fibrillation were significant predictors of a diagnosis of LVO. Additional features, such as more advanced age, can point towards a more likely diagnosis of acute stroke rather than a stroke mimicking condition.
Results of the diagnostic accuracy analysis of the proposed model show that a correct treatment decision would have been made in 70% of LVO cases and 100% of patients with other types of acute ischaemic stroke that were not caused by LVO. Subjects with a LVO in the posterior circulation are likely to be missed due to the poorer sensitivity of TCD ultrasound and clinical assessment tools in this group [22,35,40].
A haemorrhagic focus was detected on transcranial grey-scale/TCD ultrasound only in 50% of confirmed cases, mainly in central structures, such as basal ganglia. In agreement with previously reported studies , haemorrhages were likely to be missed if located in the cortical areas, posterior fossa, or in other cerebral structures that cannot be reached by ultrasound through the transtemporal window (for example, the thalamic lesions in cases 15 and 47, Additional file 1). Clinical assessment can therefore provide additional valuable information, for example, history of anticoagulant therapy, active brain tumour, and high systolic blood pressure  that would point towards suspected intracranial haemorrhage even in the absence of haemorrhagic foci on transcranial grey-scale ultrasound. A decision not to initiate reperfusion therapy would have been made based on transcranial grey-scale/TCD ultrasound and clinical assessment findings in all cases of intracranial haemorrhage, including those with insufficient acoustic window.
By making an effort to shorten the time interval from stroke symptom onset to delivery of IV thrombolysis, it is highly important to avoid providing this therapy to patients with conditions other than stroke. As demonstrated by Tsivgoulis et al (2015), about 15% of all patients treated with IV thrombolysis actually have stroke mimics. An inappropriate administration of reperfusion therapy could potentially lead to serious complications, such as intracranial and extracranial bleeding  but the risks are relatively low except when haemorrhage is present. In the present study, the highest rate of incorrect treatment decisions was in the stroke mimic group (38%). These were the subjects with a functional neurological disorder, neuropathic pain with associated weakness, and Bell’s palsy. It should be acknowledged that patients with stroke mimicking conditions might be given inappropriate treatment even in the settings of a tertiary care stroke centre . A correct treatment decision was made in all cases of TIA.
Overall performance of the proposed model based on a combination of transcranial grey-scale/TCD ultrasound and clinical assessment was better when compared with a similar system based on clinical findings alone. Interestingly, in one case a stroke mimicking condition was suspected on the basis of clinical assessment and transcranial grey-scale findings, in contrast with the CT findings which reported a bifrontal subarachnoid haemorrhage. A review of the original CT scan revised the final diagnosis to a probable bifrontal angioma.
Further work is needed to refine the model to decrease false positive rates, particularly for stroke mimicking cases, and false negative rates to ensure LVO in posterior circulation are accurately detected.
As demonstrated in the theoretical modelling study by Holodinsky et al (2018), in remote and rural areas with increased transport times, patients with ischaemic stroke due to LVO might benefit from early IV thrombolysis followed by streamlined transfer to an endovascular centre (“drip and ship”) . Furthermore, the minimum 15 minute decrease in time to treatment can be achieved by offering thrombolysis in specialised stroke ambulances without increasing the risk of intracerebral haemorrhage or mortality . The current exploratory work is part of a larger ongoing research study aimed at validating a novel triage system to select subjects who would benefit from early reperfusion therapy and direct transfer to a specialised centre. Adequate sensitivity and specificity in such a triage tool could potentially justify a randomised controlled trial of the “drip and ship” model with remotely supported specialist interpretation of the data and decision making.
The current study had several limitations. Firstly, the data in this exploratory study were collected from a sample size of only 50 participants, ten of which were confirmed as having LVO. Some patients with very mild or resolved symptoms might have been missed out from the present study due to early discharge. Equally, patients with a severe stroke may have been not included in the current study due to early mortality. These could potentially result in the studied cohort being unrepresentative of the wider population.
In most cases, the time interval between symptom onset and TCD ultrasound exceeded 24 hours. This could have potentially resulted in some early dynamic changes of blood flow being missed . Future work is required to recruit a larger sample with suspected acute stroke as soon as possible after symptom onset, ideally at the pre-hospital stage, to validate the findings of the current exploratory work.
A proportion of patients with acute ischaemic stroke due to LVO can present with mild neurological deficit . As demonstrated previously, 9-13% of patients with NIHSS ≤4 had a LVO detected on angiography [46,47] which can be successfully treated with endovascular therapy . The proposed triaging model has been designed to identify cases with a moderate to severe deficit that would benefit from reperfusion therapy. If based purely on clinical assessment, LVO cases with milder symptoms could be missed. We suggest that positive TCD findings might potentially decrease the rate of false negatives.
Angiography was not used as a reference test for detecting LVO as it is not routinely performed in this study centre at present. Therefore, further assessment with CT or magnetic resonance angiography would be recommended to confirm the diagnosis of a major intracranial vessel occlusion. MRI diffusion-weighted imaging would be required to confirm the diagnosis of an AIS and to exclude a stroke mimicking condition in those cases where CT imaging was negative.
Multivariate analysis has not been performed as part of the current interim analysis due to the low sample size, however further data analysis on a larger population would be required using a multivariate model which may allow more accurate predictions. Validation in an external cohort is advisable to test the generalisability of the proposed model.
An important and well recognised technical limitation of transcranial grey-scale/TCD ultrasound is the insufficient temporal acoustic window, which has been shown to occur in around 8% of the European general population  to 29% in the Oriental general population . It is more commonly seen in elderly subjects, especially in women over 50 years old . In our study, an insufficient window was seen in a slightly higher proportion of participants - about 40%. This may be explained by the fact that stroke patients who were generally older were recruited. However, an insufficient window only precluded a treatment decision in 4/50 (8%) patients. Further work to optimise ultrasound probe design and low-frequency insonation may be justified.