Introduction

Use of CT imaging is considered the gold standard diagnostic test to distinguish between an ischemic and a hemorrhagic stroke.[1] In areas with inadequate resources, a majority of stroke patients do not have immediate access to CT imaging. A Malaysian national report showed that in 2010, there were 52 machines in 134 public hospitals (39%). In private hospitals, only 44% had direct access to CT imaging.[2] Access to CT imaging is also hindered by the limited availability of ambulances to transport patients. There were 793 functioning ambulances throughout the country in 2010. This equated to a low 0.28 per 10,000 population[3] when compared to the expected 1 for every 10,000 population in high income countries.[4]

This limitation of resources is a major challenge to stroke care in case of time constraints. A delay in diagnosis reduces the eligibility of patients with an ischemic stroke for thrombolytic therapy. Previously, scores to differentiate between the types of stroke were developed based on clinical parameters to accommodate for the shortage of CT machines. Among the scores available include the Siriraj Stroke Score (SSS)[5], the Guys’ Hospital Score or Allen Score[6], the Besson Score[7] and the Greek Stroke Score[8]. Although several validation studies concluded that the scores were not sensitive enough in their detection of hemorrhage to replace CT imaging[9–11], there was a consistent trend of higher predictive abilities of the SSS to rule out a hemorrhagic stroke and thus, increases the chance of detecting an ischemic stroke.[10] Nevertheless, there remains a need to assess the ability of the SSS to identify ischemic stroke patients who are potentially eligible for thrombolytic therapy in the Malaysian population. Instead of replacing CT machines, the SSS is anticipated to act as a triage for prioritization of CT imaging.

This study was therefore conducted to examine the predictive value of the Siriraj Stroke Score to identify patients who are likely to have an ischemic stroke and are potentially eligible for thrombolytic therapy. The identification of these patients would allow prioritization of urgent CT imaging and increase the number of patients that can be treated with thrombolytic therapy.

Methods

The Siriraj Stroke Score (SSS)

For each patient, the SSS was calculated. Clinical variables which are needed for this score are listed in Table 1. Some symptoms are not available in the registry. We substituted them with comparable variables: ‘angina’ was replaced with ‘ischemic heart disease’, and instead of ‘intermittent claudication’, we took ‘peripheral artery disease’. Data were obtained via routine examination of patients during their arrival in the hospitals. History of comorbidities was verified with their past medical records.

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Table 1. Variables in the Original Siriraj Stroke Score.

https://doi.org/10.1371/journal.pone.0165330.t001

Clinicians who developed the original SSS score proposed two cut-off values: <-1 for ischemic stroke and >1 for hemorrhagic stroke.[5] For patients who score between -1 and 1, a distinction between ischemic and hemorrhagic stroke cannot be made. The equation for the original score is:

Results

Baseline Characteristics

Of 2176 patients who were included, 57% were males. The mean age was 62 (SD: 12) years (Table 2). Cardiovascular risk factors were common: nearly three quarters of patients had hypertension (73%), 40% with diabetes mellitus and 28% had dyslipidemia. Only 4% of the included patients had a history of atrial fibrillation whereas almost 50% of them were current smokers. Mean blood pressure upon arrival was 171mmHg (SD:36) for systolic and 94mmHg (SD:21) for diastolic. The median door-to-scan time was 4 hours (IQR: 1;14) and the median time taken for patients to arrive in the emergency departments was 2 hours (IQR: 1;3).

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Table 2. Baseline Characteristics.

https://doi.org/10.1371/journal.pone.0165330.t002

Use of the Recalibrated Siriraj Stroke Score in Prioritization of CT Imaging

In the present cohort, 73% (n = 1594) of the patients had an ischemic stroke. Only one third of these ischemic stroke patients (33%) who were potentially eligible for thrombolytic therapy received CT imaging within the therapeutic window period of 4.5 hours.

Table 3 provides results of the application of the recalibrated SSS for identification of an ischemic stroke. Depending on the choice of cut-off values, results differ. At a threshold of 0 (SSS equal or higher than 0 defines a hemorrhagic stroke), 95% (n = 1519) of the ischemic stroke patients would have been correctly diagnosed, thus prioritized for urgent CT imaging.

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Table 3. Application of the Recalibrated Siriraj Stroke Score at Different Thresholds.

https://doi.org/10.1371/journal.pone.0165330.t003

By applying the recalibrated SSS, 83% of the cohort would have been sent for urgent CT imaging. Of those, 84% would have had an ischemic stroke and 16% would have been diagnosed with a hemorrhagic stroke. Around 5% of the ischemic stroke patients would not have immediate CT imaging (Table 3).

Results from the additional analysis where the inclusion time frame was expanded from 4.5 hours to 6 hours (n = 2658) showed similar results to the above (S4 Table).

Discussion

Despite arriving within the therapeutic time for thrombolytic therapy, two-thirds of the ischemic stroke patients did not receive urgent CT imaging by 4.5 hours. This delay in diagnosis inevitably eliminate their potential eligibility for thrombolytic therapy. With the recalibrated SSS, 95% of patients with an ischemic stroke who were potentially eligible for thrombolytic therapy, could be prioritized for urgent CT imaging.

Our results on the discriminative power of the SSS were comparable with two validation studies who had reported an AUC of 0.78 (95% CI: 0.75–0.82)[22] and 0.80(95% CI not given)[23]. Previous studies including a study of smaller sample size from Malaysia reported that the original SSS has failed to achieve a high sensitivity to detect hemorrhagic stroke.[9–11,24] This is particularly so in Western countries.[25,26] Nevertheless, higher specificities for the score were found. This increases the predictive ability of the score to identify an ischemic stroke. For example, Mwita et al[10] in a systematic review reported consistently higher specificities of the SSS with a range from 65%–99% compared to its corresponding sensitivities in 18 validation studies. This is in agreement with our specificity findings. The specificity for the recalibrated score was further improved with a choice of a different cut-off value. Moreover, parallel to our aims, some of the studies[22,27] supported the use of the higher predictive rule-out ability of the SSS to detect ischemic stroke patients in areas with insufficient resources.

Previous validation studies focused on the ability of the SSS to replace CT imaging.[5,9–11,22] Here, we propose to use this score to prioritize patients who are likely to have an ischemic stroke and are potentially eligible for thrombolytic therapy for urgent CT imaging. Up to the present time, only few hospitals in the country are administering thrombolytic therapy. Reasons for this poor uptake include strict exclusion criteria such as prior use of Vitamin K antagonist, uncertainty over its benefit for elderly patients and patients with mild or very severe stroke and most importantly, a narrow therapeutic window time.[28] Although this is a similar picture globally[29], lack of infrastructure is often an additional barrier to the administration of this therapy. The present study focuses on an aspect which is common in developing regions; time delays resulting from a shortage of CT machines. Other criteria which deny patients from their eligibility for thrombolytic therapy were not taken into account in our selection of the best patients for prioritization of CT imaging.

Establishing a clinical diagnosis of an ischemic stroke with the SSS will thus, allow prioritization of the right patients for the right treatment at the right time. Moreover, there are only 5 clinical variables needed with the SSS; all easily retrieved during initial assessment of patients with symptoms of stroke. The simplicity of this score and its practical application has been commended in several studies.[5,10] Nevertheless, we are aware that the recalibrated SSS may not be easily memorized or applied without a calculator. Future implementation of this score with a possible smartphone application will be useful.

Our study had a sufficient sample size to validate the score. We performed multiple imputations to minimize possible biases from missing data. Moreover, instead of developing a new score, we chose to revise the original SSS by applying updating methods. In this respect, the score was adjusted to the new validated population without losing prior information from the development dataset.[20,30] One limitation of the study is the lack of information on stroke-mimicking diagnoses. Nevertheless, a huge majority of patients with stroke symptoms do have a diagnosis of a stroke. Previous studies showed varying rates of stroke mimics from 9–19%[31–33]. Selection bias from our selection of cohort should therefore be minimal.

There are a few important points to be emphasized with regards to the score. First, there is no intention to deprive patients from CT imaging. All suspected-for-stroke patients should receive CT imaging for diagnostic purposes. Our target patients for prioritization are ischemic stroke patients who reach the hospital within 4.5 hours because there is a tight time constraint to maximize the benefits from thrombolytic therapy. In our cohort, despite having a similar median duration of time taken to arrive at the hospital from stroke onset, patients with hemorrhagic stroke were found to have a shorter door-to-scan time in comparison to ischemic stroke patients. The median door-to-scan time was 2 hours (IQR:1;8) for the former and twice as long for the latter. While we acknowledge the urgency of a surgical procedure for patients who are suspected of a subarachnoid hemorrhage, to our best knowledge, there is no specific window period to perform surgical coiling or clipping.[34,35]

Second, the aim of this score is to guide decisions and not to overrule clinical concerns. Other factors which may influence a physician’s judgment in prioritizing patients who are suspected of a stroke for immediate CT imaging include age, other comorbidities and severity of the condition. Third, this score was recalibrated to the Asian or specifically, the Malaysian population. Differences in terms of prevalence of hemorrhagic stroke and other cardiovascular risk factors between populations may limit the generalizability of the score’s utility. The performance of this recalibrated score should be tested prior to its application in clinical practice for other populations. Fourth and most importantly, at the cut-off value chosen, 5% of ischemic stroke cases were underdiagnosed. We took the threshold of 0 to minimize this proportion of patients and at the same time, finding the best balance between false positives and false negatives. This may be less than ideal but in places that lack infrastructures, choices have to be made and we consider this as the best alternative available. Preferences of choosing specific cut-off values may differ according to the availability of resources in respective regions. With the threshold chosen, we would have to prioritize 83% of patients for urgent CT imaging. While prioritization improves efficiency in hospitals with limited CT machines, foreseeable challenges lie in hospitals without CT machines that require inter-hospital transfers for urgent CT imaging. One would be the capacity to transport these patients to hospitals with CT machines available. Should a shortage in this aspect occur, cut-off values would have to be reduced but, at the expense of a higher proportion of missed ischemic stroke cases for urgent CT imaging. Another relevant point to note is the influence of the duration for inter-hospital transfers on the eligibility for thrombolytic therapy. Having said that, about 50% of the suspected patients in our cohort arrived at the hospital within 2 hours from the onset of their symptoms. Priorities therefore, should be given to these patients once they scored below 0 (suspected ischemic stroke) for immediate stabilization and transfer for urgent CT imaging.

Conclusions

While the best option is still to have immediate access to CT imaging for every stroke patient, a shortage of CT machines would probably remain as a problem in the near future. Prioritization with the Siriraj Stroke Score aims to reduce the issues of insufficient resources. More importantly, its application is targeted to optimize stroke care especially for ischemic stroke patients with time-dependent therapy.

Supporting Information

Acknowledgments

We thank the Director General of Ministry of Health, Malaysia for his permission to publish this manuscript. We are grateful to Dr. Peter Zuithoff from the Julius Support for his expert statistical advices. Our sincere thanks also goes to personnel from all participating hospitals for their contribution in the data collection.